Substituted benzamides and methods of use thereof

ABSTRACT

The invention provides compounds having the general formula I: (i) and pharmaceutically acceptable salts thereof, wherein the variables R A , R AA , subscript n, ring A, X 2 , L, subscript m, X 1 , ring B, R 1 , and R N  have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority of provisional U.S.Application No. 62/315,469 filed 30 Mar. 2016, which is herebyincorporated by reference in its entirety.

FIELD OF INVENTION

The present invention relates to organic compounds useful for therapyand/or prophylaxis in a mammal, and in particular to inhibitors ofsodium channel (e.g., NAV1.7) that are useful for treating sodiumchannel-mediated diseases or conditions, such as pain, as well as otherdiseases and conditions associated with the mediation of sodiumchannels.

Voltage-gated sodium channels, transmembrane proteins that initiateaction potentials in nerve, muscle and other electrically excitablecells, are a necessary component of normal sensation, emotions, thoughtsand movements (Catterall, W. A., Nature (2001), Vol. 409, pp. 988-990).These channels consist of a highly processed alpha subunit that isassociated with auxiliary beta subunits. The pore-forming alpha subunitis sufficient for channel function, but the kinetics and voltagedependence of channel gating are in part modified by the beta subunits(Goldin et al., Neuron (2000), Vol. 28, pp. 365-368).Electrophysiological recording, biochemical purification, and molecularcloning have identified ten different sodium channel alpha subunits andfour beta subunits (Yu, F. H., et al., Sci. STKE (2004), 253; and Yu, F.H., et al., Neurosci. (2003), 20:7577-85).

The hallmarks of sodium channels include rapid activation andinactivation when the voltage across the plasma membrane of an excitablecell is depolarized (voltage-dependent gating), and efficient andselective conduction of sodium ions through conducting pores intrinsicto the structure of the protein (Sato, C., et al., Nature (2001),409:1047-1051). At negative or hyperpolarized membrane potentials,sodium channels are closed. Following membrane depolarization, sodiumchannels open rapidly and then inactivate. Channels only conductcurrents in the open state and, once inactivated, have to return to theresting state, favoured by membrane hyperpolarization, before they canreopen. Different sodium channel subtypes vary in the voltage range overwhich they activate and inactivate as well as their activation andinactivation kinetics.

The sodium channel family of proteins has been extensively studied andshown to be involved in a number of vital body functions. Research inthis area has identified variants of the alpha subunits that result inmajor changes in channel function and activities, which can ultimatelylead to major pathophysiological conditions. The members of this familyof proteins are denoted NaV1.x, where x=1 to 9. NaV1.1 and NaV1.2 arehighly expressed in the brain (Raymond, C. K., et al., J. Biol. Chem.(2004). 279(44):46234-41) and are vital to normal brain function. Someloss of function mutations in NaV1.1 in humans result in epilepsy,apparently because many of these channels are expressed in inhibitoryneurons (Yu, F. H., et al., Nat Neurosci (2006), 9 (9), 1142-9). Thus,block of NaV1.1 in the CNS may be counter-productive because it canproduce hyperexcitability.

However, NaV1.1 is also expressed in the peripheral nervous system andblock may afford analgesic activity.

NaV1.3 is expressed primarily in the fetal central nervous system. It isexpressed at very low levels or not at all in the peripheral nervoussystem, but expression is upregulated in the dorsal horn sensory neuronsof rats after nervous system injury (Hains, B. D., et al., J. Neurosci.(2003), 23(26):8881-92). Thus, it is an inducible target for treatmentof pain following nerve injury.

NaV1.4 is expressed primarily in skeletal muscle (Raymond, C. K., etal., op. cit.). Mutations in this gene have been shown to have profoundeffects on muscle function including paralysis, (Tamaoka A., Intern.Med. (2003), (9):769-70).

NaV1.5, is expressed mainly in cardiac myocytes (Raymond, C. K., et al.,op. cit.), including atria, ventricles, the sino-atrial node,atrio-ventricular node and cardiac Purkinje fibers. The rapid upstrokeof the cardiac action potential and the rapid impulse conduction throughcardiac tissue is due to the opening of NaV1.5. Abnormalities in thefunction of NaV1.5 can result in the genesis of a variety of cardiacarrhythmias. Mutations in human NaV1.5 result in multiple arrhythmicsyndromes, including, for example, long QT3 (LQT3), Brugada syndrome(BS), an inherited cardiac conduction defect, sudden unexpectednocturnal death syndrome (SUNDS) and sudden infant death syndrome (SIDS)(Liu, H., et al., Am. J. Pharmacogenomics (2003), 3(3): 173-9). Sodiumchannel blocker therapy has been used extensively in treating cardiacarrhythmias.

NaV1.6 is a widely distributed voltage-gated sodium channel foundthroughout the central and peripheral nervous systems. It is expressedat high density in the nodes of Ranvier of myelinated neurons (Caldwell,J. H., et al., Proc. Natl. Acad. Sci. USA (2000), 97(10): 5616-20).

NaV1.7 is a tetrodotoxin-sensitive voltage-gated sodium channel encodedby the gene SCN9A. Human NaV1.7 was first cloned from neuroendocrinecells (Klugbauer, N., et al., 1995 EMBO J., 14 (6): 1084-90.) and ratNaV1.7 was cloned from a pheochromocytoma PC12 cell line (Toledo-Aral,J. J., et al., Proc. Natl. Acad. Sci. USA (1997), 94:1527-1532) and fromrat dorsal root ganglia (Sangameswaran, L., et al., (1997), J. Biol.Chem., 272 (23): 14805-9). NaV1.7 is expressed primarily in theperipheral nervous system, especially nocieptors and olfactory neuronsand sympathetic neurons. The inhibition, or blocking, of NaV1.7 has beenshown to result in analgesic activity. Knockout of NaV1.7 expression ina subset of sensory neurons that are predominantly nociceptive resultsin resistance to inflammatory pain (Nassar, et al., op. cit.). Likewise,loss of function mutations in humans results in congenital indifferenceto pain (CIP), in which the individuals are resistant to bothinflammatory and neuropathic pain (Cox, J. J., et al., Nature (2006);444:894-898; Goldberg, Y. P., et al., Clin. Genet. (2007); 71:311-319).Conversely, gain of function mutations in NaV1.7 have been establishedin two human heritable pain conditions, primary erythromelalgia andfamilial rectal pain, (Yang, Y., et al., J. Med. Genet. (2004),41(3):171-4). In addition, a single nucleotide polymorphism (R1150W)that has very subtle effects on the time- and voltage-dependence ofchannel gating has large effects on pain perception (Estacion, M., etal., 2009. Ann Neurol 66: 862-6; Reimann, F., et al., Proc Natl Acad SciUSA (2010), 107: 5148-53). About 10% of the patients with a variety ofpain conditions have the allele conferring greater sensitivity to painand thus might be more likely to respond to block of NaV1.7. BecauseNaV1.7 is expressed in both sensory and sympathetic neurons, one mightexpect that enhanced pain perception would be accompanied bycardiovascular abnormalities such as hypertension, but no correlationhas been reported. Thus, both the CIP mutations and SNP analysis suggestthat human pain responses are more sensitive to changes in NaV1.7currents than are perturbations of autonomic function.

NaV1.8 is expressed primarily in sensory ganglia of the peripheralnervous system, such as the dorsal root ganglia (Raymond, C. K., et al.,op. cit.). There are no identified human mutations for NaV1.8 thatproduce altered pain responses. NaV1.8 differs from most neuronal NaV'sin that it is insensitive to block by tetrodotoxin. Thus, one canisolate the current carried by this channel with tetrodotoxin. Thesestudies have shown that a substantial portion of total sodium current isNaV1.8 in some dorsal root ganglion neurons (Blair, N. T., et al., JNeurosci (2002), 22: 10277-90). Knock-down of NaV1.8 in rats has beenachieved by using antisense DNA or small interfering RNAs and virtuallycomplete reversal of neuropathic pain was achieved in the spinal nerveligation and chronic constriction injury models (Dong, X. W., et al.,Neuroscience (2007), 146: 812-21; Lai J., et al. Pain (2002), 95:143-52). Thus, NaV1.8 is considered a promising target for analgesicagents based upon the limited tissue distribution of this NaV isoformand the analgesic activity produced by knock-down of channel expression.

NaV1.9 is also a tetrodotoxin insensitive, sodium channel expressedprimarily in dorsal root ganglia neurons (Dib-Hajj, S. D., et al. (seeDib-Hajj, S. D., et al., Proc. Natl. Acad. Sci. USA (1998),95(15):8963-8). It is also expressed in enteric neurons, especially themyenteric plexus (Rugiero, F., et al., J Neurosci (2003), 23: 2715-25).The limited tissue distribution of this NaV isoform suggests that it maybe a useful target for analgesic agents (Lai, J., et al., op. cit.;Wood, J. N., et al., op. cit.; Chung, J. M., et al., op. cit.).Knock-out of NaV1.9 results in resistance to some forms of inflammatorypain (Amaya, F., et al., J Neurosci (2006), 26: 12852-60; Priest, B. T.,et al., Proc Natl Acad Sci USA (2005), 102: 9382-7).

This closely related family of proteins has long been recognized astargets for therapeutic intervention. Sodium channels are targeted by adiverse array of pharmacological agents. These include neurotoxins,antiarrhythmics, anticonvulsants and local anesthetics (England, S., etal., Future Med Chem (2010), 2: 775-90; Termin, A., et al., AnnualReports in Medicinal Chemistry (2008), 43: 43-60). All of the currentpharmacological agents that act on sodium channels have receptor siteson the alpha subunits. At least six distinct receptor sites forneurotoxins and one receptor site for local anesthetics and relateddrugs have been identified (Cestéle, S., et al., Biochimie (2000), Vol.82, pp. 883-892).

The small molecule sodium channel blockers or the local anesthetics andrelated antiepileptic and antiarrhythmic drugs interact with overlappingreceptor sites located in the inner cavity of the pore of the sodiumchannel (Catterall, W. A., Neuron (2000), 26:13-25). Amino acid residuesin the S6 segments from at least three of the four domains contribute tothis complex drug receptor site, with the IVS6 segment playing thedominant role. These regions are highly conserved and as such mostsodium channel blockers known to date interact with similar potency withall channel subtypes. Nevertheless, it has been possible to producesodium channel blockers with therapeutic selectivity and a sufficienttherapeutic window for the treatment of epilepsy (e.g., lamotrignine,phenytoin and carbamazepine) and certain cardiac arrhythmias (e.g.,lignocaine, tocainide and mexiletine). However, the potency andtherapeutic index of these blockers is not optimal and have limited theusefulness of these compounds in a variety of therapeutic areas where asodium channel blocker would be ideally suited.

Sodium channel blockers have been shown to be useful in the treatment ofpain, including acute, chronic, inflammatory and/or neuropathic pain(see, e.g., Wood, J. N., et al., J. Neurobiol. (2004), 61(1), 55-71.Preclinical evidence demonstrates that sodium channel blockers cansuppress neuronal firing in peripheral and central sensory neurons, andit is via this mechanism that they are considered to be useful forrelieving pain. In some instances, abnormal or ectopic firing canoriginal from injured or otherwise sensitized neurons. For example, ithas been shown that sodium channels can accumulate in peripheral nervesat sites of axonal injury and may function as generators of ectopicfiring (Devor et al., J. Neurosci. (1993), 132: 1976). Changes in sodiumchannel expression and excitability have also been shown in animalmodels of inflammatory pain where treatment with proinflammatorymaterials (CFA, Carrageenan) promoted pain-related behaviors andcorrelated with increased expression of sodium channel subunits (Gouldet al., Brain Res., (1999), 824(2): 296-99; Black et al., Pain (2004),108(3): 237-47). Alterations in either the level of expression ordistribution of sodium channels, therefore, may have a major influenceon neuronal excitability and pain-related behaviors.

Controlled infusions of lidocaine, a known sodium channel blocker,indicate that the drug is efficacious against neuropathic pain, but hasa narrow therapeutic index. Likewise, the orally available localanesthetic, mexiletine, has dose-limiting side effects (Wallace, M. S.,et al., Reg. Anesth. Pain Med. (2000), 25: 459-67). A major focus ofdrug discovery targeting voltage-gated sodium channels has been onstrategies for improving the therapeutic index. One of the leadingstrategies is to identify selective sodium channel blockers designed topreferentially block NaV1.7, NaV1.8, NaV1.9 and/or NaV1.3. These are thesodium channel isoforms preferentially expressed in sensory neurons andunlikely to be involved in generating any dose-limiting side effects.For example, there is concern that blocking of NaV1.5 would bearrhythmogenic, so that selectivity of a sodium channel blocker againstNaV1.5 is viewed as highly desirable. Furthermore, nearly 700 mutationsof the SCN1A gene that codes for NaV1.1 have been identified in patientswith Severe Myoclonic Epilepsy of Infancy (SMEI), making this the mostcommonly mutated gene in human epilepsy. Half of these mutations resultin protein truncation (Meisler, M. H., et al., The Journal of Physiology(2010), 588: 1841-8). Thus, selectivity of a sodium channel blockeragainst NaV1.1 is also desirable.

In addition to the strategies of identifying selective sodium channelblockers, there is the continuing strategy of identifying therapeuticagents for the treatment of neuropathic pain. There has been some degreeof success in treating neuropathic pain symptoms by using medicationsoriginally approved as anticonvulsants, such as gabapentin, and morerecently pregabalin. However, pharmacotherapy for neuropathic pain hasgenerally had limited success for a variety of reasons: sedation,especially by drugs first developed as anticonvulsants oranti-depressants, addiction or tachyphylaxis, especially by opiates, orlack of efficacy, especially by NSAIDs and anti-inflammatory agents.Consequently, there is still a considerable need to explore noveltreatment modalities for neuropathic pain, which includes, but is notlimited to, post-herpetic neuralgia, trigeminal neuralgia, diabeticneuropathy, chronic lower back pain, phantom limb pain, and painresulting from cancer and chemotherapy, chronic pelvic pain, complexregional pain syndrome and related neuralgias.

International Patent Application Numbers PCT/IB2012/056031,PCT/IB2012/056032, PCT/US2013/042111 PCT/US2013/049423,PCT/US2014/029004, PCT/US2014/028796, PCT/CN2014/092269, andPCT/US2015/039413 relate to compounds that are useful for treatingsodium channel-mediated diseases or conditions, such as pain.

There are a limited number of effective sodium channel blockers for thetreatment of pain with a minimum of adverse side effects which arecurrently in the clinic. There is also an unmet medical need to treatneuropathic pain and other sodium channel associated pathological stateseffectively and without adverse side effects due to the blocking ofsodium channels not involved in nociception. The present inventionprovides methods to meet these critical needs.

SUMMARY OF THE INVENTION

In one aspect the present invention provides for novel compounds. In afirst embodiment of such compounds (Embodiment 1; abbreviated as “E1”)the invention provides for a compound of formula I:

or a salt thereof, wherein:

R¹ is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, 3-20membered carbocycle, C-linked 3-20 membered heterocycle, or—NR^(1A)R^(1B), wherein R^(1A) and R^(1B) are each independentlyselected from the group consisting of hydrogen, C₁₋₈ alkyl, C₁₋₈ alkoxy,and wherein R^(1A) and R^(1B) are optionally combined to form a 3-20membered heterocycle; and wherein R¹ is optionally substituted with from1 to 5 substituents selected from the group consisting of C₁₋₄ alkyl,C₁₋₄ haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂, —NR^(R1a)R^(R1b),—OR^(R1a), —SR^(R1a), —Si(R^(R1a))₃ and C₃₋₆ carbocycle; wherein R^(R1a)and R^(R1b) are independently selected from the group consisting ofhydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl;

R^(N) is hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl;

L is a linker selected from the group consisting of C₁₋₄ alkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene, wherein L is optionally substituted withfrom 1 to 3 substituents selected from the group consisting of ═O, C₁₋₄alkyl, halo, and C₁₋₄ haloalkyl;

the subscript m is 0 or 1;

X¹ and X² are each independently selected from the group consisting ofabsent, —O—, —S(O)—, —S(O)₂— and —N(R^(X))— wherein R^(x) is H, C₁₋₈alkyl, C₁₋₈ alkanoyl, or —S(O)₂(C₁₋₈ alkyl), and wherein if thesubscript m is 0 then one of X¹ or X² is absent;

the subscript n is 0, 1, 2, 3, 4, or 5;

the ring A is a 3-20 membered carbocyclyl, a 6-20 membered aryl, a 5-20membered heteroaryl, or a 3-20 membered heterocyclyl;

each R^(AA) is independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ heteroalkyl, CN, F, Cl, Br and I; and

R^(A) is selected from the group consisting of absent, CN, F, Cl, Br, IR^(A1)O—(X^(RB))—, (3-20 membered aryl)-(X^(RA))—, (3-20 memberedheteroaryl)-(X^(RA))—, (3-20 membered carbocycle)-(X^(RA))—, (3-20membered heterocycle)-(X^(RA))—, —R^(A2), and —S(O)₂—R^(A2), whereinsaid 3-20 membered aryl, 3-20 membered heteroaryl, 3-20 memberedcarbocycle and 3-20 membered heterocycle of R^(A) is optionallysubstituted with from 1 to 5 substitutents selected from, F, Cl, Br, I,—NH₂, —OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,C₁₋₄(halo)alkoxy, C₁₋₄ alkylamino, C₁₋₄ dialkylamino, C₁4 alkanoyl, C₁₋₄alkyl-OC(═O)—, C₁₋₄ alkyl-S(O)₂—, C₃₋₆ carbocycle, and phenyl that isoptionally substituted with one or more substituents selected fromfluoro, chloro, and bromo; R^(A1) is selected from the group consistingof hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl,phenyl and benzyl; R^(A2) is selected from the group consisting of C₁₋₈alkyl that is optionally substituted with one or more substituentsselected from oxo (═O), fluoro, amino, C₁₋₄ alkylamino and C₁₋₄dialkylamino; X^(RA) is selected from the group consisting of absent,—O—, —S—, —N(H)—, —N(C₁₋₄ alkyl)-, —S(O)—, —S(O)₂—, —C(═O)—, C₁₋₄alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene;X^(RB) is selected from the group consisting of absent, C₁₋₄ alkylene,C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene; wherein anyC₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄ alkynyleneof X^(RA) or X^(RB) is optionally substituted with 1 to 3 substituentsselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄heteroalkyl, oxo (═O), hydroxy, and phenyl that is optionallysubstituted with 1 to 5 substitutents selected from, F, Cl, Br, I, —NH₂,—OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,C₁₋₄(halo)alkoxy, C₁₋₄ alkylamino and C₁₋₄ dialkylamino; or whereinX^(RA) or X^(RB) is optionally substituted with 2 substituents thatcombine to form a 3-5 membered carbocycle or a 3-5 membered heterocycle;

the ring B is selected from:

D¹ is N or C(R^(D1));

D³ is N or C(R^(D3));

R^(D1), R^(D2), R^(D3) and R^(D4) are each independently selected fromthe group consisting of H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈haloalkyl,C₁₋₈ alkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocycle, phenyland 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected fromN, O and S, wherein said 5-6 membered heteroaryl is further optionallysubstituted with from 1 to 3 substituents selected from F, Cl, Br, I,—CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ alkoxy;

R²² and R²³ are each independently selected from the group consisting ofH, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy;

R²⁴ is selected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, 3-12 membered carbocycle, 3-12membered heterocycle, phenyl and 5-6 membered heteroaryl comprising 1 to3 heteroatoms selected from N, O and S, wherein said 5-6 memberedheteroaryl is further optionally substituted with from 1 to 3 R⁵substituents selected from F, Cl, Br, I, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyland C₁₋₄ alkoxy;

R³² and R³³ are each independently selected from the group consisting ofH, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy;

R³⁴ is selected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, 3-12 memberedcarbocycle, 3-12 membered heterocycle, phenyl and 5-6 memberedheteroaryl comprising 1 to 3 heteroatoms selected from N, O and S,wherein said 5-6 membered heteroaryl is further optionally substitutedwith from 1 to 3 substituents selected from F, Cl, Br, I, —CN, C₁₋₄alkyl, C₁₋₄ haloalkyl and C₁₋₄ alkoxy;

R⁴² is selected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy;

R⁴³ is selected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy;

R⁴⁴ is selected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy; and

R⁴⁵ is selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₁₋₈ alkoxy, and 3-12 membered cycloalkyl, wherein said C₁₋₈alkoxy, and C₃₋₈ cycloalkyl is optionally substituted with 1-3substituents selected from F, Cl, Br and I.

Further embodiments (E2-E49) of the first embodiment of compounds of theinvention, are described below.

E2. The compound of E1, wherein R¹ is selected from the group consistingof C₁₋₈ alkyl, C₁₋₈ haloalkyl, 3-12 membered carbocycle, C-linked 3-12membered heterocycle, and —NR^(1A)R^(1B), wherein R^(1A) and R^(1B) areeach independently selected from the group consisting of C₁₋₈ alkyl andC₁₋₈ alkoxy, and wherein R^(1A) and R^(1B) are optionally combined toform a 3 to 6 membered heterocyclic ring; and wherein R¹ is optionallysubstituted with from 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, F, Cl, Br, I, —OH, —OR^(R1a),—SR^(R1a), —Si(R^(R1a))₃, and C₃₋₅ carbocycle; wherein R^(R1a) andR^(R1b) are independently selected from the group consisting ofhydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl.

E3. The compound of E1, wherein R¹ is selected from the group consistingof C₁₋₈ alkyl, 3-6 membered carbocycle, and —NR^(1A)R^(1B), whereinR^(1A) and R^(1B) are combined to form a 3 to 6 membered heterocyclicring selected from the group consisting of aziridine, azetidine,pyrrolidine, piperidine and morpholino; wherein R¹ is optionallysubstituted with from 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, F, Cl, Br, I, —OH, —OR^(R1a),SR^(R1a), —Si(R^(R1a))₃, and C₃₋₅ carbocycle; wherein R^(R1a) andR^(R1b) are independently selected from the group consisting ofhydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl.

E4. The compound of E1, wherein R¹ is methyl, cyclopropyl,cyclopropylmethyl, 1-azetidinyl, 1-methylcycloprop-1-yl, difluoromethyl,N-methylamino, ethyl, 2-methoxyeth-1-yl, 2-trimethylsilyleth-1-yl,propyl, 1,1,1-trifluoroprop-3-yl, butyl, morpholino, pyrrolidino, or3-fluoroazetidin-1-yl.

E5. The compound of E1, wherein R¹ is methyl, cyclopropyl, 1-azetidinylor 2-methoxyethyl.

E6. The compound of E1, E2, E3, E4, or E5, wherein X¹ is —O— or —N(H)—;X² is absent; the subscript m is 1; and -(L)- is an optionallysubstituted group selected from the group consisting of C₁₋₄ alkylene,C₂₋₄ alkenylene or C₂₋₄ alkynylene.

E7. The compound of E1, E2, E3, E4, or E5, wherein X¹ is —O— or —N(H)—;X² is absent; the subscript m is 1; and -(L)- is selected from the groupconsisting of —CH₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—, —CH₂—C(H)(CH₃)—,—C(H)(CH₃)—CH₂—, —CH₂CH₂CH₂—, —CH₂—C(H)(CH₃)—CH₂— or —CH₂CH₂CH₂CH₂—.

E8. The compound of E1, E2, E3, E4, or E5, wherein X¹ is —O—; thesubscript m is 1 and -(L)- is —CH₂— or —CH₂—CH₂—.

E9. The compound of E1, E2, E3, E4, or E5, wherein X¹ is absent; X² is—O— or —N(H)—; the subscript m is 1; and -(L)- is selected from thegroup consisting of —CH₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—,—CH₂—C(H)(CH₃)—, —C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—, —CH₂—C(H)(CH₃)—CH₂—,and —CH₂CH₂CH₂CH₂—.

E10. The compound of E1, E2, E3, E4, or E5, wherein X¹ and X² is absent;the subscript m is 1; and -(L)- is selected from the group consisting of—CH₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—, —CH₂—C(H)(CH₃)—,—C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—, —CH₂—C(H)(CH₃)—CH₂—, and —CH₂CH₂CH₂CH₂—.

E11. The compound of E1, E2, E3, E4, or E5, wherein m is 0; X¹ isselected from —O—, and —N(H)—; and X² is absent.

E12. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, or E11,wherein the ring A represents a 6-10 membered aryl or a 5-10 memberedheteroaryl comprising 1 to 3 heteroatoms selected from N, O and S.

E13. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, or E11,wherein the ring A is selected from the group consisting of 3-20membered carbocycle, 3-20 membered heterocycle, 6-12 membered aryl, and5-12 membered heteroaryl.

E14. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, or E11,wherein the ring A is selected from the group consisting of 3-20membered carbocycle, 3-20 membered heterocycle, 6-12 membered aryl, anda 5-12 membered heteroaryl.

E15. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, or E11,wherein the ring A is a 3-12 membered heterocycle comprising a nitrogenatom and further optionally comprising 1-2 heteroatoms selected from N,O and S.

E16. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, or E11,wherein the ring A is a 3-15 membered carbocyclyl, a 6-12 membered aryl,a 5-12 membered heteroaryl, or a 3-15 membered heterocyclyl.

E17. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, or E11,wherein A is optionally substituted and is selected from azetidine,pyrrolidine, piperidine, morpholine, homopiperazine, and piperazine.

E18. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, or E17, wherein the ring B is:

R^(D1) is selected from the group consisting of H, F, Cl, Br, I, —CN,C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, 3-12 membered cycloalkyl and3-12 membered heterocycle, wherein said 3-12 membered cycloalkyl and3-12 membered heterocycle is optionally substituted with 1-3substituents selected from F, Cl, Br I, and C₁₋₈ alkoxy;

R^(D2) is selected from the group consisting of H, F, Cl, Br, I, —CN,C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy;

R^(D3) is selected from the group consisting of H, F, Cl, Br, I, —CN,C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy; and

R^(D4) is selected from the group consisting of H, F, Cl, Br, I, —CN,C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy.

E19. The compound of E18, wherein R^(D2) is H.

E20. The compound of E18 or E19, R^(D3) is F, Cl, or Br.

E21. The compound of E18 or E19, wherein R^(D3) is F.

E22. The compound of E18 or E19, wherein R^(D3) is cyclopropyl.

E23. The compound of E18, E19, E20, E21, or E22, wherein R^(D4) is H.

E24. The compound of E18, E19, E20, E21, E22, or E23, wherein R^(D1) isF, Cl, cyclopropyl, or 2-methoxy-3-pyridyl.

E25. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, or E11,wherein:

is selected from the group consisting of:

E26. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, or E11,wherein:

is selected from the group consisting of:

E27. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, or E26,wherein R^(AA) is selected from the group consisting of methyl,trifluoromethyl, ethyl, CN, F, Cl, Br, and I.

E28. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, or E26,wherein R^(AA) is selected from the group consisting of methyl,trifluoromethyl, ethyl, F, Cl, Br, and I.

E29. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E26,E27, or E28, wherein R^(A) is selected from the group consisting ofphenyl-(X^(RA))—, wherein said phenyl is optionally substituted withfrom 1 to 5 substitutents selected from, F, Cl, Br, —NH₂, —OH, —CN,—NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄dialkylamino, phenyl, C₁₋₄ alkanoyl, C₁₋₄ alkyl-OC(═O)— and 3-6 memberedcarbocycle; and wherein X^(RA) is selected from the group consisting ofabsent, —O—, —S—, —N(H)—, —N(C₁₋₄ alkyl)-, C₁₋₄ alkylene, C₁₋₄heteroalkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene; and wherein X^(RA)is optionally substituted with 1 to 3 substituents selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ heteroalkyl, andphenyl that is optionally substituted with 1 to 5 substitutents selectedfrom, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, C₁₋₄ alkylamino and C₁₋₄ dialkylamino.

E30. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E26,E27, or E28, wherein R^(A) is phenyl-(X^(RA))—, wherein said phenyl isoptionally substituted with from 1 to 5 substitutents selected from, F,Cl, C₁₋₄ alkyl, —CN, C₃₋₆ carbocycle and C₁₋₄ haloalkyl; wherein X^(RA)is selected from the group consisting of absent and C₁₋₄ alkylene; andwherein X^(RA) is optionally substituted with 1 to 3 substituentsselected from the group consisting of C₁₋₄ alkyl and phenyl that isoptionally substituted with 1 to 5 substitutents selected from, F, Cl,C₁₋₄ alkyl, and C₁₋₄ haloalkyl.

E31. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E26,E27, or E28, wherein R^(A) is R^(A1)O—(X^(RB))—; R^(A1) is selected fromthe group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈haloalkyl, C₃₋₈ cycloalkyl, phenyl and benzyl; and X^(RB) is selectedfrom the group consisting of absent and C₁₋₄ alkylene that is optionallysubstituted with 1 to 3 substituents selected from the group consistingof C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ heteroalkyl, oxo (═O), and phenylthat is optionally substituted with 1 to 5 substitutents selected from,F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄(halo)alkoxy, C₁₋₄ alkylamino and C₁₋₄ dialkylamino.

E32. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E26,E27, or E28, wherein R^(A) is selected from the group consisting of:

E33. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E26,E27, or E28, wherein R^(A) is selected from the group consisting of

E34. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E26,E27, or E28, wherein RA is selected from the group consisting of phenyl,phenylmethyl, pyrazolyl, pyrazolylmethyl, cyclobutyl, cyclohexylmethyl,cyclopentyl, cyclopentylmethyl, cyclobutyl, cyclobutylmethyl,pyrimidinyl, pyrimidinylmethyl, pyrazinyl, pyrazinylmethyl, pyridazinyl,pyridazinylmethyl, indolinyl, indolinylmethyl, isoindolinyl, andisoindolinylmethyl and wherein R^(A) is optionally substituted with from1 to 5 substitutents selected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁-4(halo)alkoxy, C₁₋₄alkylamino, C₁₋₄ dialkylamino, C₁₋₄ alkanoyl, C₁₋₄ alkyl-OC(═O)—, C₁₋₄alkyl-S(O)₂—, 3-6 membered carbocycle, and phenyl that is optionallysubstituted with one or more substituents selected from fluoro, chloro,and bromo.

E35. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E26,E27, or E28, wherein R^(A) is selected from the group consisting ofR^(A1)O—(X^(RB))—, 6-12 membered aryl-(X^(RA))—, 5-12 memberedheteroaryl-(X^(RA))—, 3-12 membered carbocycle-(X^(RA))— and 3-12membered heterocycle-(X^(RA))—, wherein said 6-12 membered aryl, 5-12membered heteroaryl, 3-12 membered carbocycle and 3-12 memberedheterocycle of R^(A) is optionally substituted with from 1 to 5substitutents selected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄ dialkylamino,phenyl, C₁₋₄ alkanoyl, C₁₋₄ alkyl-OC(═O)— and C₃₋₆ carbocycle; R^(A1) isselected from the group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈alkenyl, C₁₋₈ haloalkyl, 3-8 membered cycloalkyl, phenyl and benzyl;X^(RA) is selected from the group consisting of absent, —O—, —S—,—N(H)—, —N(C₁₋₄ alkyl)-, C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; and X^(RB) is selected from the groupconsisting of absent, C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; wherein any C₁₋₄ alkylene, C₁₋₄heteroalkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene of X^(RA) or X^(RB)is optionally substituted with 1 to 3 substituents selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₁₋₄ heteroalkyl.

E36. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E26,E27, or E28, wherein RA is selected from the group consisting ofR^(A1)O—(X^(RB))—, 6-12 membered aryl-(X^(RA))—, 5-12 memberedheteroaryl-(X^(RA))—, 3-12 membered carbocycle-(X^(RA))— and 3-12membered heterocycle-(X^(RA))—, wherein said 6-12 membered aryl, 5-12membered heteroaryl, 3-12 membered carbocycle and 3-12 memberedheterocycle of R^(A) is optionally substituted with from 1 to 5substitutents selected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄ dialkylamino,phenyl, C₁₋₄ alkanoyl, C₁₋₄ alkyl-OC(═O)— and 3-6 membered carbocycle;R^(A1) is selected from the group consisting of hydrogen, C₁₋₈ alkyl,C₂₋₈ alkenyl, C₁₋₈ haloalkyl, 3-6 membered cycloalkyl, phenyl andbenzyl; X^(RA) is selected from the group consisting of absent, —O—,—S—, —N(H)—, —N(C₁₋₄ alkyl)-, C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; and X^(RB) is selected from the groupconsisting of absent, C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; wherein any C₁₋₄ alkylene, C₁₋₄heteroalkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene of X^(RA) or X^(RB)is optionally substituted with 1 to 3 substituents selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₁₋₄ heteroalkyl.

E37. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E26,E27, or E28, wherein R^(A) is 6-12 membered aryl-(X^(RA))—, wherein said6-12 membered aryl of R^(A) is optionally substituted with from 1 to 5substitutents selected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁-4(halo)alkoxy, C₁₋₄ alkylamino,C₁₋₄ dialkylamino, phenyl, C₁₋₄ alkanoyl, C₁₋₄ alkyl-OC(═O)—, C₁₋₄alkyl-S(O)₂—, and 3-6 membered carbocycle; and X^(RA) is selected fromthe group consisting of —C(═O)—, C₁₋₄ alkylene, C₁₋₄ heteroalkylene,C₂₋₄ alkenylene and C₂₋₄ alkynylene; wherein any C₁₋₄ alkylene, C₁₋₄heteroalkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene of X^(RA) isoptionally substituted with 1 to 3 substituents selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ heteroalkyl, oxo (═O),and phenyl that is optionally substituted with 1 to 5 substitutentsselected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁-4(halo)alkoxy, C₁₋₄ alkylamino and C₁₋₄dialkylamino.

E38. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E26,E27, or E28, wherein R^(A) is phenyl —(X^(RA))—, wherein said phenyl isoptionally substituted with from 1 to 5 substitutents selected from, F,Cl, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄(halo)alkoxy;and X^(RA) is C₁₋₄ alkylene that is optionally substituted with 1 to 3substituents selected from the group consisting of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ heteroalkyl, oxo (═O), and phenyl that is optionallysubstituted with 1 to 5 substitutents selected from, F, Cl, Br, I, —NH₂,—OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,C₁-4(halo)alkoxy, C₁₋₄ alkylamino and C₁₋₄ dialkylamino.

E39. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E24, E25, E26, E27, E28, E29, E30, E31, E32, E33,E34, E35, E36, E37, or E38, wherein the compound has the formula Ia:

E40. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E24, E25, E26, E27, E28, E29, E30, E31, E32, E33,E34, E35, E36, E37, or E38, which is a compound of formula Ib:

E41. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E24, E25, E26, E27, E28, E29, E30, E31, E32, E33,E34, E35, E36, E37, or E38, which is a compound of formula Ic:

E42. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E24, E25, E26, E27, E28, E29, E30, E31, E32, E33,E34, E35, E36, E37, or E38, wherein the compound has the formula Id:

E43. The compound of E39, E40, E41, or E42 wherein R¹ is methyl, ethyl,cyclopropyl, or 1-azetidinyl.

E44. The compound of E39, E40, E41, E42, or E43 wherein —X²-(L)_(m)-X¹—is —O—, —CH₂—, —CH₂—O—, or —CH₂CH₂—O—.

E45. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E26, E27, E28,E29, E30, E31, E32, E33, E34, E35, E36, E37, or E38, wherein:

E46. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E26, E27, E28,E29, E30, E31, E32, E33, E34, E35, E36, E37, or E38, wherein:

E47. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E26, E27, E28,E29, E30, E31, E32, E33, E34, E35, E36, E37, or E38, wherein:

has the formula:

E48. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E18,E19, E20, E21, E22, E23, or E24, wherein:

is selected from the group consisting of:

E49. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E24, E25, E26, E27, E28, E29, E30, E31, E32, E33,E34, E35, E36, E37, E38, E39, E40, E41, E42, E43, E44, E45, E46, E47, orE48, wherein the group:

is selected from the group consisting of:

E50. The compound of E1 which is selected from:

and salts thereof.

In another aspect the present invention provides for a pharmaceuticalcomposition comprising a compound of formula I or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect the present invention provides for a method oftreating a disease or condition in a mammal selected from the groupconsisting of pain, depression, cardiovascular diseases, respiratorydiseases, and psychiatric diseases, and combinations thereof, whereinthe method comprises administering to the mammal in need thereof atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof. In another aspect of thepresent invention said disease or condition is selected from the groupconsisting of neuropathic pain, inflammatory pain, visceral pain, cancerpain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain,childbirth pain, labor pain, neurogenic bladder, ulcerative colitis,chronic pain, persistent pain, peripherally mediated pain, centrallymediated pain, chronic headache, migraine headache, sinus headache,tension headache, phantom limb pain, dental pain, peripheral nerveinjury or a combination thereof. In another aspect of the presentinvention said disease or condition is selected from the groupconsisting of pain associated with HIV, HIV treatment inducedneuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia, heatsensitivity, tosarcoidosis, irritable bowel syndrome, Crohns disease,pain associated with multiple sclerosis (MS), amyotrophic lateralsclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis,rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmaldystonia, myasthenia syndromes, myotonia, malignant hyperthermia, cysticfibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolardepression, anxiety, schizophrenia, sodium channel toxi relatedillnesses, familial erythromelalgia, primary erythromelalgia, familialrectal pain, cancer, epilepsy, partial and general tonic seizures,restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection underischaemic conditions cause by stroke or neural trauma, tach-arrhythmias,atrial fibrillation and ventricular fibrillation.

In another aspect the present invention provides for a method oftreating pain in a mammal by the inhibition of ion flux through avoltage-dependent sodium channel in the mammal, wherein the methodcomprises administering to the mammal in need thereof a therapeuticallyeffective amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof.

In another aspect the present invention provides for a method ofdecreasing ion flux through a voltage-dependent sodium channel in a cellin a mammal, wherein the method comprises contacting the cell with acompound of formula I, or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides for a method oftreating pruritus in a mammal, wherein the method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of formula I, or a pharmaceutically acceptable saltthereof.

In another aspect the present invention provides for a method oftreating cancer in a mammal, wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount acompound of formula I, or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides for a method oftreating, but not preventing, pain in a mammal, wherein the methodcomprises administering to the mammal in need thereof a therapeuticallyeffective amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof. In another aspect of the present invention thepain is selected from the group consisting of neuropathic pain,inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumapain, surgical pain, post-surgical pain, childbirth pain, labor pain,neurogenic bladder, ulcerative colitis, chronic pain, persistent pain,peripherally mediated pain, centrally mediated pain, chronic headache,migraine headache, sinus headache, tension headache, phantom limb pain,dental pain, peripheral nerve injury or a combination thereof. Inanother aspect the present invention the pain is associated with adisease or condition selected from the group consisting of HIV, HIVtreatment induced neuropathy, trigeminal neuralgia, post-herpeticneuralgia, eudynia, heat sensitivity, tosarcoidosis, irritable bowelsyndrome, Crohns disease, pain associated with multiple sclerosis (MS),amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheralneuropathy, arthritis, rheumatoid arthritis, osteoarthritis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,malignant hyperthermia, cystic fibrosis, pseudoaldosteronism,rhabdomyolysis, hypothyroidism, bipolar depression, anxiety,schizophrenia, sodium channel toxi related illnesses, familialerythromelalgia, primary erythromelalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscause by stroke or neural trauma, tach-arrhythmias, atrial fibrillationand ventricular fibrillation.

In another aspect the present invention provides for a method oftreating, but not preventing, acute pain or chronic pain in a mammal,wherein the method comprises administering to the mammal in need thereofa therapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof.

In another aspect the present invention provides for a method oftreating, but not preventing, neuropathic pain or inflammatory pain in amammal, wherein the method comprises administering to the mammal in needthereof a therapeutically effective amount of a compound of formula I,or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides for a method for thetreatment or prophylaxis of pain, depression, cardiovascular disease,respiratory disease, or psychiatric disease, or a combinations thereof,in an animal which method comprises administering an effective amount ofa compound of formula I, or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides for a compound offormula I, or a pharmaceutically acceptable salt thereof for the use asa medicament for the treatment of diseases and disorders selected fromthe group consisting of pain, depression, cardiovascular diseases,respiratory diseases, and psychiatric diseases, or a combinationthereof.

In another aspect the present invention provides for the use of acompound of formula I, or a pharmaceutically acceptable salt thereof forthe manufacture of a medicament for the treatment of diseases anddisorders selected from the group consisting of pain, depression,cardiovascular diseases, respiratory diseases, and psychiatric diseases,or a combination thereof.

In another aspect the present invention provides for the invention asdescribed herein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the term “alkyl”, by itself or as part of anothersubstituent, means, unless otherwise stated, a straight or branchedchain hydrocarbon radical, having the number of carbon atoms designated(i.e., C₁₋₈ means one to eight carbons). Examples of alkyl groupsinclude methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl,iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and thelike. The term “alkenyl” refers to an unsaturated alkyl radical havingone or more double bonds. Similarly, the term “alkynyl” refers to anunsaturated alkyl radical having one or more triple bonds. Examples ofsuch unsaturated alkyl groups include vinyl, 2-propenyl, crotyl,2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs andisomers.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chainhydrocarbon radical, consisting of the stated number of carbon atoms andfrom one to three heteroatoms selected from the group consisting of O,N, Si and S, and wherein the nitrogen and sulfur atoms can optionally beoxidized and the nitrogen heteroatom can optionally be quaternized. Theheteroatom(s) O, N and S can be placed at any interior position of theheteroalkyl group. The heteroatom Si can be placed at any position ofthe heteroalkyl group, including the position at which the alkyl groupis attached to the remainder of the molecule. A “heteroalkyl” cancontain up to three units of unsaturation, and also include mono- andpoly-halogenated variants, or combinations thereof. Examples include—CH₂—CH₂—O—CH₃, —CH₂—CH₂—O—CF₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH═N(CH₃)—CH₃. Up to two heteroatoms can beconsecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane (including branched alkane), asexemplified by —CH₂CH₂CH₂CH₂— and —CH(CH₂)CH₂CH₂—. Typically, an alkyl(or alkylene) group will have from 1 to 24 carbon atoms, with thosegroups having 10 or fewer carbon atoms being preferred in the presentinvention. “Alkenylene” and “alkynylene” refer to the unsaturated formsof “alkylene” having double or triple bonds, respectively. “Alkylene”,“alkenylene” and “alkynylene” are also meant to include mono andpoly-halogenated variants.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical, saturated or unsaturated or polyunsaturated,derived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—, —O—CH₂—CH═CH—, —CH₂—CH═C(H)CH₂—O—CH₂— and—S—CH₂—C≡C—. For heteroalkylene groups, heteroatoms can also occupyeither or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,alkyleneamino, alkylenediamino, and the like). The term “heteroalkylene”is also meant to include mono and poly-halogenated variants.

The terms “alkoxy,” “alkylamino” and “alkylthio”, are used in theirconventional sense, and refer to those alkyl groups attached to theremainder of the molecule via an oxygen atom (“oxy”), an amino group(“amino”) or thio group, and further include mono- and poly-halogenatedvariants thereof. Additionally, for dialkylamino groups, the alkylportions can be the same or different.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. The term “(halo)alkyl” is meant to include botha “alkyl” and “haloalkyl” substituent. Additionally, the term“haloalkyl,” is meant to include monohaloalkyl and polyhaloalkyl. Forexample, the term “C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, andthe like.

The term “aryl” as used herein refers to a single all carbon aromaticring or a multiple condensed all carbon ring system wherein at least oneof the rings is aromatic. For example, in certain embodiments, an arylgroup has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbonatoms. Aryl includes a phenyl radical. Aryl also includes multiplecondensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings)having about 9 to 20 carbon atoms in which at least one ring is aromaticand wherein the other rings may be aromatic or not aromatic (i.e.,carbocycle). Such multiple condensed ring systems are optionallysubstituted with one or more (e.g., 1, 2 or 3) oxo groups on anycarbocycle portion of the multiple condensed ring system. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis to be understood that the point of attachment of a multiple condensedring system, as defined above, can be at any position of the ring systemincluding an aromatic or a carbocycle portion of the ring. Non-limitingexamples of aryl groups include, but are not limited to, phenyl,indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and thelike.

The term “carbocycle” or “carbocyclyl” refers to a single saturated(i.e., cycloalkyl) or a single partially unsaturated (e.g.,cycloalkenyl, cycloalkadienyl, etc.) all carbon ring having 3 to 7carbon atoms (i.e., (C₃-C₇)carbocycle). The term “carbocycle” or“carbocyclyl” also includes multiple condensed, saturated and partiallyunsaturated all carbon ring systems (e.g., ring systems comprising 2, 3or 4 carbocyclic rings). For example, in certain embodiments, a“carbocycle” or “carbocyclyl” has 3 to 20 members (i.e. carbon atoms), 3to 14 members, or 3 to 12 members. Accordingly, carbocycle includesmulticyclic carbocyles such as a bicyclic carbocycles (e.g., bicycliccarbocycles having about 6 to 12 carbon atoms such asbicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycycliccarbocycles (e.g., tricyclic and tetracyclic carbocycles with up toabout 20 carbon atoms). The rings of the multiple condensed ring systemcan be connected to each other via fused, spiro and bridged bonds whenallowed by valency requirements. For example, multicyclic carbocyles canbe connected to each other via a single carbon atom to form a spiroconnection (e.g., spiropentane, spiro[4,5]decane, etc), via two adjacentcarbon atoms to form a fused connection (e.g., carbocycles such asdecahydronaphthalene, norsabinane, norcarane) or via two non-adjacentcarbon atoms to form a bridged connection (e.g., norbornane,bicyclo[2.2.2]octane, etc). The “carbocycle” or “carbocyclyl” can alsobe optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups.In one embodiment the term carbocycle includes a C₃₋₁₂ carbocycle. Inone embodiment the term carbocycle includes a C₃₋₈ carbocycle. In oneembodiment the term carbocycle includes a C₃₋₆ carbocycle. In oneembodiment the term carbocycle includes a C₃₋₅ carbocycle. Non-limitingexamples of carbocycles include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, bicyclo[2.2.1]heptane, pinane,adamantane, norborene, spirocyclic C₅₋₁₂ alkane, and 1-cyclohex-3-enyl.

The term “heteroaryl” as used herein refers to a single aromatic ringthat has at least one atom other than carbon in the ring, wherein theatom is selected from the group consisting of oxygen, nitrogen andsulfur; “heteroaryl” also includes multiple condensed ring systems thathave at least one such aromatic ring, which multiple condensed ringsystems are further described below. For example, in certainembodiments, a “heteroaryl has 5 to 20 members (i.e. atoms), 5 to 14members, or 5 to 12 members. Thus, “heteroaryl” includes single aromaticrings of from about 1 to 6 carbon atoms and about 1-4 heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur. Thesulfur and nitrogen atoms may also be present in an oxidized formprovided the ring is aromatic. Exemplary heteroaryl ring systems includebut are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.“Heteroaryl” also includes multiple condensed ring systems (e.g., ringsystems comprising 2, 3 or 4 rings) wherein a heteroaryl group, asdefined above, is condensed with one or more rings selected fromheteroaryls (to form, for example, a naphthyridinyl such as1,8-naphthyridinyl), heterocycles, (to form, for example, a 1, 2, 3,4-tetrahydronaphthyridinyl such as1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form, forexample, 5,6,7,8-tetrahydroquinolyl) and aryls (to form, for example,indazolyl) to form the multiple condensed ring system. Thus, aheteroaryl (a single aromatic ring or multiple condensed ring system)has about 1-20 carbon atoms and about 1-6 heteroatoms within theheteroaryl ring. Such multiple condensed ring systems may be optionallysubstituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on thecarbocycle or heterocycle portions of the condensed ring. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis to be understood that the individual rings of the multiple condensedring system may be connected in any order relative to one another. It isalso to be understood that the point of attachment of a multiplecondensed ring system (as defined above for a heteroaryl) can be at anyposition of the multiple condensed ring system including a heteroaryl,heterocycle, aryl or carbocycle portion of the multiple condensed ringsystem. It is also to be understood that the point of attachment for aheteroaryl or heteroaryl multiple condensed ring system can be at anysuitable atom of the heteroaryl or heteroaryl multiple condensed ringsystem including a carbon atom and a heteroatom (e.g., a nitrogen).Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl,thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl,indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl,quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole and3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclo-penta[1,2-c]pyrazole.

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated ring that has at least oneatom other than carbon in the ring, wherein the atom is selected fromthe group consisting of oxygen, nitrogen and sulfur; the term alsoincludes multiple condensed ring systems that have at least one suchsaturated or partially unsaturated ring, which multiple condensed ringsystems are further described below. Thus, the term includes singlesaturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-memberedrings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur in thering. For example, in certain embodiments, a “heterocyclyl” or“heterocycle” has 3 to 20 members (i.e. atoms), 3 to 14 members, or 3 to12 members. The ring may be substituted with one or more (e.g., 1, 2 or3) oxo groups and the sulfur and nitrogen atoms may also be present intheir oxidized forms. Exemplary heterocycles include but are not limitedto azetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle”also includes multiple condensed ring systems (e.g., ring systemscomprising 2, 3 or 4 rings) wherein a single heterocycle ring (asdefined above) can be condensed with one or more groups selected fromheterocycles (to form for example a 1,8-decahydronapthyridinyl),carbocycles (to form for example a decahydroquinolyl) and aryls to formthe multiple condensed ring system. Thus, a heterocycle (a singlesaturated or single partially unsaturated ring or multiple condensedring system) has about 2-20 carbon atoms and 1-6 heteroatoms within theheterocycle ring. Such multiple condensed ring systems may be optionallysubstituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on thecarbocycle or heterocycle portions of the multiple condensed ring. Therings of the multiple condensed ring system can be connected to eachother via fused, spiro and bridged bonds when allowed by valencyrequirements. It is to be understood that the individual rings of themultiple condensed ring system may be connected in any order relative toone another. It is also to be understood that the point of attachment ofa multiple condensed ring system (as defined above for a heterocycle)can be at any position of the multiple condensed ring system including aheterocycle, aryl and carbocycle portion of the ring. It is also to beunderstood that the point of attachment for a heterocycle or heterocyclemultiple condensed ring system can be at any suitable atom of theheterocycle or heterocycle multiple condensed ring system including acarbon atom and a heteroatom (e.g., a nitrogen). In one embodiment theterm heterocycle includes a C₂₋₂₀ heterocycle. In one embodiment theterm heterocycle includes a C₂₋₇ heterocycle. In one embodiment the termheterocycle includes a C₂₋₅ heterocycle. In one embodiment the termheterocycle includes a C₂₋₄ heterocycle. Exemplary heterocycles include,but are not limited to aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl,dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl,spiro[cyclopropane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one,2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one N-methylpiperidine,imidazolidine, pyrazolidine, butyrolactam, valerolactam,imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane,thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyran,3-pyrroline, thiopyran, pyrone, tetrhydrothiophene, quinuclidine,tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane,(1s,4s)-2-azabicyclo[2.2.2]octane,(1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and pyrrolidin-2-one.

The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in someembodiments, will include both substituted and unsubstituted forms ofthe indicated radical. Preferred substituents for each type of radicalare provided below.

Substituents for the alkyl radicals (including those groups oftenreferred to as alkylene, alkenyl, alkynyl, heteroalkyl, carbocycle, andheterocyclyl) can be a variety of groups including, but not limited to,

-halogen, —OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′″C(O)NR′R″, —NR″C(O)₂R′,—NHC(NH₂)═NH, —NR C(NH₂)═NH, —NHC(NH₂)═NR′, —NR′″C(NR′R″)═N—CN,—NR′″C(NR′R″)═NOR′, —NHC(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NR′S(O)₂R″, —NR′″S(O)₂NR′R″, —CN, —NO₂, —(CH₂)₁₋₄—OR′, —(CH₂)₁₋₄—NR′R″,—(CH₂)₁₋₄—SR′, —(CH₂)₁₋₄—SiR′R″R′″, —(CH₂)₁₋₄—OC(O)R′, —(CH₂)₁₋₄—C(O)R′,—(CH₂)₁₋₄—CO₂R′, —(CH₂)₁₋₄CONR′″, in a number ranging from zero to(2m′+1), where m′ is the total number of carbon atoms in such radical.R′, R″ and R′″ each independently refer groups including, for example,hydrogen, unsubstituted C₁₋₆ alkyl, unsubstituted heteroalkyl,unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstitutedC₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₆ thioalkoxy groups, or unsubstitutedaryl-C₁₋₄ alkyl groups, unsubstituted heteroaryl, substitutedheteroaryl, among others. When R′ and R″ are attached to the samenitrogen atom, they can be combined with the nitrogen atom to form a 3-,4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include1-pyrrolidinyl and 4-morpholinyl. Other substitutents for alkylradicals, including heteroalkyl, alkylene, include for example, ═O,═NR′, ═N—OR′, ═N—CN, ═NH, wherein R′ include substituents as describedabove.

Similarly, substituents for the aryl and heteroaryl groups are variedand are generally selected from the group including, but not limited tohalogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″,—C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′, —NR′C(O)NR″R′″,—NHC(NH₂)═NH, —NR′C(NH₂)═NH, —NHC(NH₂)═NR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NR′S(O)₂R″, —N₃, perfluoro-C₁₋₄ alkoxy, andperfluoro-C₁₋₄alkyl, —(CH₂)₁₋₄—OR′, —(CH₂)₁₋₄—NR′R″, —(CH₂)₁₋₄—SR′,—(CH₂)₁₋₄—SiR′R″R′″, —(CH₂)₁₋₄—OC(O)R′, —(CH₂)₁₋₄—C(O)R′,—(CH₂)₁₋₄—CO₂R′, —(CH₂)₁₋₄CONR′R″, in a number ranging from zero to thetotal number of open valences on the aromatic ring system; and where R′,R″ and R′″ are independently selected from hydrogen, C₁₋₆ alkyl, C₃₋₆carbocycle, C₂₋₆ alkenyl, C₂₋₆ alkynyl, unsubstituted aryl andheteroaryl, (unsubstituted aryl)-C₁₋₄ alkyl, and unsubstitutedaryloxy-C₁₋₄ alkyl. Other suitable substituents include each of theabove aryl substituents attached to a ring atom by an alkylene tether offrom 1-4 carbon atoms. When a substituent for the aryl or heteroarylgroup contains an alkylene linker (e.g., —(CH₂)₁₋₄—NR′R″), the alkylenelinker includes halo variants as well. For example, the linker“—(CH₂)₁₋₄—” when used as part of a substituent is meant to includedifluoromethylene, 1,2-difluoroethylene, etc.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

As used herein, the term “chiral” refers to molecules which have theproperty of non-superimposability of the mirror image partner, while theterm “achiral” refers to molecules which are superimposable on theirmirror image partner.

As used herein, the term “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

As used herein a wavy line “

” that intersects a bond in a chemical structure indicates the point ofattachment of the bond that the wavy bond intersects in the chemicalstructure to the remainder of a molecule.

As used herein, the term “C-linked” means that the group that the termdescribes is attached the remainder of the molecule through a ringcarbon atom.

As used herein, the term “N-linked” means that the group that the termdescribes is attached to the remainder of the molecule through a ringnitrogen atom.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers can separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention can contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer can also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which canoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

As used herein, the term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

As used herein, the term “solvate” refers to an association or complexof one or more solvent molecules and a compound of the invention.Examples of solvents that form solvates include, but are not limited to,water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,and ethanolamine. The term “hydrate” refers to the complex where thesolvent molecule is water.

As used herein, the term “protecting group” refers to a substituent thatis commonly employed to block or protect a particular functional groupon a compound. For example, an “amino-protecting group” is a substituentattached to an amino group that blocks or protects the aminofunctionality in the compound. Suitable amino-protecting groups includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ)and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitable protectinggroups include acetyl and silyl. A “carboxy-protecting group” refers toa substituent of the carboxy group that blocks or protects the carboxyfunctionality. Common carboxy-protecting groups includephenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyland the like. For a general description of protecting groups and theiruse, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups inOrganic Synthesis 4^(th) edition, Wiley-Interscience, New York, 2006.

As used herein, the term “mammal” includes, but is not limited to,humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows,pigs, and sheep.

As used herein, the term “pharmaceutically acceptable salts” is meant toinclude salts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the presentinvention contain relatively acidic functionalities, base addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al., “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds can be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. As used herein the term “prodrug” refers tothose compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Prodrugs of the invention include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues, is covalently joined through an amide orester bond to a free amino, hydroxy or carboxylic acid group of acompound of the present invention. The amino acid residues include butare not limited to the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also includes phosphoserine,phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine,demosine, isodemosine, gamma-carboxyglutamate, hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, citrulline, homocysteine, homoserine,methyl-alanine, para-benzoylphenylalanine, phenylglycine,propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of the invention can be derivatized as anamide or alkyl ester. As another example, compounds of this inventioncomprising free hydroxy groups can be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. etal., (1996) Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group can be an alkyl ester optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem., (1996), 39:10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁₋₆)alkanoyloxymethyl,1-((C₁₋₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁₋₆)alkanoyloxy)ethyl,(C₁₋₆)alkoxycarbonyloxymethyl, N—(C₁₋₆)alkoxycarbonylaminomethyl,succinoyl, (C₁₋₆)alkanoyl, alpha-amino(C₁₋₄)alkanoyl, arylacyl andalpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where eachalpha-aminoacyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

Additionally, the present invention provides for metabolites ofcompounds of the invention. As used herein, a “metabolite” refers to aproduct produced through metabolism in the body of a specified compoundor salt thereof. Such products can result for example from theoxidation, reduction, hydrolysis, amidation, deamidation,esterification, deesterification, enzymatic cleavage, and the like, ofthe administered compound.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention can exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention.

The compounds of the present invention can also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the present invention alsoembraces isotopically-labeled variants of the present invention whichare identical to those recited herein, bur the for the fact that one ormore atoms are replace by an atom having the atomic mass or mass numberdifferent from the predominant atomic mass or mass number usually foundin nature for the atom. All isotopes of any particular atom or elementas specified are contemplated within the scope of the compounds of theinvention, and their uses. Exemplary isotopes that can be incorporatedin to compounds of the invention include istopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine,such as ²H (“D”), ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P ³³P,³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I. Certain isotopically labeled compounds ofthe present invention (e.g., those labeled with ³H or ¹⁴C) are useful incompound and/or substrate tissue distribution assays. Tritiated (³H) andcarbon-14 (¹⁴C) isotopes are usefule for their ease of preparation anddetectability. Further substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸Fare useful for positron emission tomography (PET) studies to examinesubstrate receptor occupancy. Isotopically labeled compounds of thepresent inventions can generally be prepared by following proceduresanalogous to those disclosed in the Schemes and/or in the Examplesherein below, by substituting an isotopically labeled reagent for anon-isotopically labeled reagent.

The terms “treat” and “treatment” refer to both therapeutic treatmentand/or prophylactic treatment or preventative measures, wherein theobject is to prevent or slow down (lessen) an undesired physiologicalchange or disorder, such as, for example, the development or spread ofcancer. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease or disorder, stabilized (i.e., notworsening) state of disease or disorder, delay or slowing of diseaseprogression, amelioration or palliation of the disease state ordisorder, and remission (whether partial or total), whether detectableor undetectable. “Treatment” can also mean prolonging survival ascompared to expected survival if not receiving treatment. Those in needof treatment include those already with the disease or disorder as wellas those prone to have the disease or disorder or those in which thedisease or disorder is to be prevented.

The phrase “therapeutically effective amount” or “effective amount”means an amount of a compound of the present invention that (i) treatsor prevents the particular disease, condition, or disorder, (ii)attenuates, ameliorates, or eliminates one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevents or delaysthe onset of one or more symptoms of the particular disease, condition,or disorder described herein. For cancer therapy, efficacy can, forexample, be measured by assessing the time to disease progression (TTP)and/or determining the response rate (RR).

The term “bioavailability” refers to the systemic availability (i.e.,blood/plasma levels) of a given amount of drug administered to apatient. Bioavailability is an absolute term that indicates measurementof both the time (rate) and total amount (extent) of drug that reachesthe general circulation from an administered dosage form.

In another embodiment, the compound is selected from compounds offormula I as described in the Examples herein and salts thereof.

Synthesis of Compounds

Compounds of formula (I) may be prepared by the process illustrated inScheme 1.

Pharmaceutical Compositions and Administration

In addition to one or more of the compounds provided above (orstereoisomers, geometric isomers, tautomers, solvates, metabolites,isotopes, pharmaceutically acceptable salts, or prodrugs thereof), theinvention also provides for compositions and medicaments comprising acompound of formula I or and embodiment thereof and at least onepharmaceutically acceptable carrier, diluent or excipient. Thecompositions of the invention can be used to selectively inhibit NaV1.7in patients (e.g, humans).

The term “composition,” as used herein, is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In one embodiment, the invention provides for pharmaceuticalcompositions (or medicaments) comprising a compound of formula I or anembodiment thereof, and its stereoisomers, geometric isomers, tautomers,solvates, metabolites, isotopes, pharmaceutically acceptable salts, orprodrugs thereof) and a pharmaceutically acceptable carrier, diluent orexcipient. In another embodiment, the invention provides for preparingcompositions (or medicaments) comprising compounds of the invention. Inanother embodiment, the invention provides for administering compoundsof formula I or its embodiments and compositions comprising compounds offormula I or an embodiment thereof to a patient (e.g., a human patient)in need thereof.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The effective amount of the compound tobe administered will be governed by such considerations, and is theminimum amount necessary to inhibit NaV1.7 activity as required toprevent or treat the undesired disease or disorder, such as for example,pain. For example, such amount may be below the amount that is toxic tonormal cells, or the mammal as a whole.

In one example, the therapeutically effective amount of the compound ofthe invention administered parenterally per dose will be in the range ofabout 0.01-100 mg/kg, alternatively about e.g., 0.1 to 20 mg/kg ofpatient body weight per day, with the typical initial range of compoundused being 0.3 to 15 mg/kg/day. The daily does is, in certainembodiments, given as a single daily dose or in divided doses two to sixtimes a day, or in sustained release form. In the case of a 70 kg adulthuman, the total daily dose will generally be from about 7 mg to about1,400 mg. This dosage regimen may be adjusted to provide the optimaltherapeutic response. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, intracerebral, intraocular, intralesional orsubcutaneous administration.

The compositions comprising compounds of formula I or an embodimentthereof are normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition. A typicalformulation is prepared by mixing a compound of the present inventionand a diluent, carrier or excipient. Suitable diluents, carriers andexcipients are well known to those skilled in the art and are describedin detail in, e.g., Ansel, Howard C., et al., Ansel's PharmaceuticalDosage Forms and Drug Delivery Systems. Philadelphia: Lippincott,Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: TheScience and Practice of Pharmacy. Philadelphia: Lippincott, Williams &Wilkins, 2000; and Rowe, Raymond C. Handbook of PharmaceuticalExcipients. Chicago, Pharmaceutical Press, 2005. The formulations mayalso include one or more buffers, stabilizing agents, surfactants,wetting agents, lubricating agents, emulsifiers, suspending agents,preservatives, antioxidants, opaquing agents, glidants, processing aids,colorants, sweeteners, perfuming agents, flavoring agents, diluents andother known additives to provide an elegant presentation of the drug(i.e., a compound of the present invention or pharmaceutical compositionthereof) or aid in the manufacturing of the pharmaceutical product(i.e., medicament).

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water and the like. The particularcarrier, diluent or excipient used will depend upon the means andpurpose for which a compound of the present invention is being applied.Solvents are generally selected based on solvents recognized by personsskilled in the art as safe (GRAS) to be administered to a mammal. Ingeneral, safe solvents are non-toxic aqueous solvents such as water andother non-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Theformulations can also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Aactive pharmaceutical ingredient of the invention (e.g., compound offormula I or an embodiment thereof) can also be entrapped inmicrocapsules prepared, for example, by coacervation techniques or byinterfacial polymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams &Wilkins, Philidelphia, Pa.

Sustained-release preparations of a compound of the invention (e.g.,compound of formula I or an embodiment thereof) can be prepared.Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of formula I or an embodiment thereof, which matrices are inthe form of shaped articles, e.g., films, or microcapsules. Examples ofsustained-release matrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983),non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater.Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers suchas the LUPRON DEPOT™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate) andpoly-D-(−)-3-hydroxybutyric acid (EP 133,988A). Sustained releasecompositions also include liposomally entrapped compounds, which can beprepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci.U.S.A. 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A.77:4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A).Ordinarily, the liposomes are of the small (about 200-800 Angstroms)unilamelar type in which the lipid content is greater than about 30 mol% cholesterol, the selected proportion being adjusted for the optimaltherapy.

The formulations include those suitable for the administration routesdetailed herein. The formulations can conveniently be presented in unitdosage form and can be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams &Wilkins, Philidelphia, Pa. Such methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more accessory ingredients.

In general the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers,diluents or excipients or finely divided solid carriers, diluents orexcipients, or both, and then, if necessary, shaping the product. Atypical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. The formulations can beprepared using conventional dissolution and mixing procedures. Forexample, the bulk drug substance (i.e., compound of the presentinvention or stabilized form of the compound (e.g., complex with acyclodextrin derivative or other known complexation agent) is dissolvedin a suitable solvent in the presence of one or more of the excipientsdescribed above. A compound of the present invention is typicallyformulated into pharmaceutical dosage forms to provide an easilycontrollable dosage of the drug and to enable patient compliance withthe prescribed regimen.

In one example, compounds of formula I or an embodiment thereof may beformulated by mixing at ambient temperature at the appropriate pH, andat the desired degree of purity, with physiologically acceptablecarriers, i.e., carriers that are non-toxic to recipients at the dosagesand concentrations employed into a galenical administration form. The pHof the formulation depends mainly on the particular use and theconcentration of compound, but preferably ranges anywhere from about 3to about 8. In one example, a compound of formula I (or an embodimentthereof) is formulated in an acetate buffer, at pH 5. In anotherembodiment, the compounds of formula I or an embodiment thereof aresterile. The compound may be stored, for example, as a solid oramorphous composition, as a lyophilized formulation or as an aqueoussolution.

Formulations of a compound of the invention (e.g., compound of formula Ior an embodiment thereof) suitable for oral administration can beprepared as discrete units such as pills, capsules, cachets or tabletseach containing a predetermined amount of a compound of the invention.

Compressed tablets can be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets can bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets canoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs can be prepared for oral use. Formulationsof a compound of the invention (e.g., compound of formula I or anembodiment thereof) intended for oral use can be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions can contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients can be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets can be uncoated or can be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period.

For example, a time delay material such as glyceryl monostearate orglyceryl distearate alone or with a wax can be employed.

An example of a suitable oral administration form is a tablet containingabout 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250mg, 300 mg and 500 mg of the compound of the invention compounded withabout 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose,about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mgmagnesium stearate. The powdered ingredients are first mixed togetherand then mixed with a solution of the PVP. The resulting composition canbe dried, granulated, mixed with the magnesium stearate and compressedto tablet form using conventional equipment. An example of an aerosolformulation can be prepared by dissolving the compound, for example5-400 mg, of the invention in a suitable buffer solution, e.g. aphosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride,if desired. The solution may be filtered, e.g., using a 0.2 micronfilter, to remove impurities and contaminants.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientcan be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients can be formulated in a creamwith an oil-in-water cream base. If desired, the aqueous phase of thecream base can include a polyhydric alcohol, i.e., an alcohol having twoor more hydroxyl groups such as propylene glycol, butane 1,3-diol,mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400)and mixtures thereof. The topical formulations can desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethyl sulfoxide and relatedanalogs.

The oily phase of the emulsions of this invention can be constitutedfrom known ingredients in a known manner. While the phase can comprisemerely an emulsifier, it desirably comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

In one aspect of topical applications, it is desired to administer aneffective amount of a pharmaceutical composition according to theinvention to target area, e.g., skin surfaces, mucous membranes, and thelike, which are adjacent to peripheral neurons which are to be treated.This amount will generally range from about 0.0001 mg to about 1 g of acompound of the invention per application, depending upon the area to betreated, whether the use is diagnostic, prophylactic or therapeutic, theseverity of the symptoms, and the nature of the topical vehicleemployed. A preferred topical preparation is an ointment, wherein about0.001 to about 50 mg of active ingredient is used per cc of ointmentbase. The pharmaceutical composition can be formulated as transdermalcompositions or transdermal delivery devices (“patches”). Suchcompositions include, for example, a backing, active compound reservoir,a control membrane, liner and contact adhesive. Such transdermal patchesmay be used to provide continuous pulsatile, or on demand delivery ofthe compounds of the present invention as desired.

Aqueous suspensions of a compound of the invention (e.g., compound offormula I or an embodiment thereof) contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, croscarmellose, povidone, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth and gum acacia, and dispersing or wetting agents such asa naturally occurring phosphatide (e.g., lecithin), a condensationproduct of an alkylene oxide with a fatty acid (e.g., polyoxyethylenestearate), a condensation product of ethylene oxide with a long chainaliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

Formulations of a compound of the invention (e.g., compound of formula Ior an embodiment thereof) can be in the form of a sterile injectablepreparation, such as a sterile injectable aqueous or oleaginoussuspension. This suspension can be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation canalso be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, such as a solution in1,3-butanediol or prepared as a lyophilized powder. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile fixed oilscan conventionally be employed as a solvent or suspending medium. Forthis purpose any bland fixed oil can be employed including syntheticmono- or diglycerides. In addition, fatty acids such as oleic acid canlikewise be used in the preparation of injectables.

The amount of active ingredient that can be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans cancontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which can varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion can contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which can contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which can include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration can be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration can beprepared according to conventional methods and can be delivered withother therapeutic agents such as compounds heretofore used in thetreatment of disorders as described below.

The formulations can be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

When the binding target is located in the brain, certain embodiments ofthe invention provide for a compound of formula I (or an embodimentthereof) to traverse the blood-brain barrier. Certain neurodegenerativediseases are associated with an increase in permeability of theblood-brain barrier, such that a compound of formula I (or an embodimentthereof) can be readily introduced to the brain. When the blood-brainbarrier remains intact, several art-known approaches exist fortransporting molecules across it, including, but not limited to,physical methods, lipid-based methods, and receptor and channel-basedmethods.

Physical methods of transporting a compound of formula I (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, circumventing the blood-brain barrier entirely, or bycreating openings in the blood-brain barrier.

Circumvention methods include, but are not limited to, direct injectioninto the brain (see, e.g., Papanastassiou et al., Gene Therapy9:398-406, 2002), interstitial infusion/convection-enhanced delivery(see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91:2076-2080,1994), and implanting a delivery device in the brain (see, e.g., Gill etal., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford.

Pharmaceutical). Methods of creating openings in the barrier include,but are not limited to, ultrasound (see, e.g., U.S. Patent PublicationNo. 2002/0038086), osmotic pressure (e.g., by administration ofhypertonic mannitol (Neuwelt, E. A., Implication of the Blood-BrainBarrier and its Manipulation, Volumes I and 2, Plenum Press, N.Y.,1989)), and permeabilization by, e.g., bradykinin or permeabilizer A-7(see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and5,686,416).

Lipid-based methods of transporting a compound of formula I (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, encapsulating the a compound of formula I (or an embodimentthereof) in liposomes that are coupled to antibody binding fragmentsthat bind to receptors on the vascular endothelium of the blood-brainbarrier (see, e.g., U.S. Patent Application Publication No.2002/0025313), and coating a compound of formula I (or an embodimentthereof) in low-density lipoprotein particles (see, e.g., U.S. PatentApplication Publication No. 2004/0204354) or apolipoprotein E (see,e.g., U.S. Patent Application Publication No. 2004/0131692).

Receptor and channel-based methods of transporting a compound of formulaI (or an embodiment thereof) across the blood-brain barrier include, butare not limited to, using glucocorticoid blockers to increasepermeability of the blood-brain barrier (see, e.g., U.S. PatentApplication Publication Nos. 2002/0065259, 2003/0162695, and2005/0124533); activating potassium channels (see, e.g., U.S. PatentApplication Publication No. 2005/0089473), inhibiting ABC drugtransporters (see, e.g., U.S. Patent Application Publication No.2003/0073713); coating a compound of formula I (or an embodimentthereof) with a transferrin and modulating activity of the one or moretransferrin receptors (see, e.g., U.S. Patent Application PublicationNo. 2003/0129186), and cationizing the antibodies (see, e.g., U.S. Pat.No. 5,004,697).

For intracerebral use, in certain embodiments, the compounds can beadministered continuously by infusion into the fluid reservoirs of theCNS, although bolus injection may be acceptable. The inhibitors can beadministered into the ventricles of the brain or otherwise introducedinto the CNS or spinal fluid. Administration can be performed by use ofan indwelling catheter and a continuous administration means such as apump, or it can be administered by implantation, e.g., intracerebralimplantation of a sustained-release vehicle. More specifically, theinhibitors can be injected through chronically implanted cannulas orchronically infused with the help of osmotic minipumps. Subcutaneouspumps are available that deliver proteins through a small tubing to thecerebral ventricles. Highly sophisticated pumps can be refilled throughthe skin and their delivery rate can be set without surgicalintervention. Examples of suitable administration protocols and deliverysystems involving a subcutaneous pump device or continuousintracerebroventricular infusion through a totally implanted drugdelivery system are those used for the administration of dopamine,dopamine agonists, and cholinergic agonists to Alzheimer's diseasepatients and animal models for Parkinson's disease, as described byHarbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al.,Mov. Disord. 2: 143, 1987.

A compound of formula I (or an embodiment thereof) used in the inventionare formulated, dosed, and administered in a fashion consistent withgood medical practice. Factors for consideration in this context includethe particular disorder being treated, the particular mammal beingtreated, the clinical condition of the individual patient, the cause ofthe disorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners. A compound of formula I (or anembodiment thereof) need not be, but is optionally formulated with oneor more agent currently used to prevent or treat the disorder inquestion. The effective amount of such other agents depends on theamount of a compound of the invention present in the formulation, thetype of disorder or treatment, and other factors discussed above.

These are generally used in the same dosages and with administrationroutes as described herein, or about from 1 to 99% of the dosagesdescribed herein, or in any dosage and by any route that isempirically/clinically determined to be appropriate.

For the prevention or treatment of disease, the appropriate dosage of acompound of formula I (or an embodiment thereof) (when used alone or incombination with other agents) will depend on the type of disease to betreated, the properties of the compound, the severity and course of thedisease, whether the compound is administered for preventive ortherapeutic purposes, previous therapy, the patient's clinical historyand response to the compound, and the discretion of the attendingphysician. The compound is suitably administered to the patient at onetime or over a series of treatments. Depending on the type and severityof the disease, about 1 g/kg to 15 mg/kg (e.g., 0.1 mg/kg-10 mg/kg) ofcompound can be an initial candidate dosage for administration to thepatient, whether, for example, by one or more separate administrations,or by continuous infusion. One typical daily dosage might range fromabout 1 μg kg to 100 mg/kg or more, depending on the factors mentionedabove. For repeated administrations over several days or longer,depending on the condition, the treatment would generally be sustaineduntil a desired suppression of disease symptoms occurs. One exemplarydosage of a compound of formula I (or an embodiment thereof) would be inthe range from about 0.05 mg/kg to about 10 mg/kg. Thus, one or moredoses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg, or 10 mg/kg (or anycombination thereof) may be administered to the patient. Such doses maybe administered intermittently, e.g., every week or every three weeks(e.g., such that the patient receives from about two to about twenty,or, e.g., about six doses of the antibody). An initial higher loadingdose, followed by one or more lower doses may be administered. Anexemplary dosing regimen comprises administering an initial loading doseof about 4 mg/kg, followed by a weekly maintenance dose of about 2 mg kgof the compound. However, other dosage regimens may be useful. Theprogress of this therapy is easily monitored by conventional techniquesand assays.

Other typical daily dosages might range from, for example, about 1 g/kgto up to 100 mg/kg or more (e.g., about 1 μg kg to 1 mg/kg, about 1μg/kg to about 5 mg/kg, about 1 mg kg to 10 mg/kg, about 5 mg/kg toabout 200 mg/kg, about 50 mg/kg to about 150 mg/mg, about 100 mg/kg toabout 500 mg/kg, about 100 mg/kg to about 400 mg/kg, and about 200 mg/kgto about 400 mg/kg), depending on the factors mentioned above.Typically, the clinician will administer a compound until a dosage isreached that results in improvement in or, optimally, elimination of,one or more symptoms of the treated disease or condition. The progressof this therapy is easily monitored by conventional assays. One or moreagent provided herein may be administered together or at different times(e.g., one agent is administered prior to the administration of a secondagent). One or more agent may be administered to a subject usingdifferent techniques (e.g., one agent may be administered orally, whilea second agent is administered via intramuscular injection orintranasally). One or more agent may be administered such that the oneor more agent has a pharmacologic effect in a subject at the same time.Alternatively, one or more agent may be administered, such that thepharmacological activity of the first administered agent is expiredprior the administration of one or more secondarily administered agents(e.g., 1, 2, 3, or 4 secondarily administered agents).

Indications and Methods of Treatment

The compounds of the invention modulate, preferably inhibit, ion fluxthrough a voltage-dependent sodium channel in a mammal, (e.g, a human).Any such modulation, whether it be partial or complete inhibition orprevention of ion flux, is sometimes referred to herein as “blocking”and corresponding compounds as “blockers” or “inhibitors”. In general,the compounds of the invention modulate the activity of a sodium channeldownwards by inhibiting the voltage-dependent activity of the sodiumchannel, and/or reduce or prevent sodium ion flux across a cell membraneby preventing sodium channel activity such as ion flux.

The compounds of the invention inhibit the ion flux through avoltage-dependent sodium channel. In one aspect, the compounds are stateor frequency dependent modifers of the sodium channels, having a lowaffinity for the rested/closed state and a high affinity for theinactivated state. Without being bound by any particular theory, it isthought that these compounds are likely to interact with overlappingsites located in the inner cavity of the sodium conducting pore of thechannel similar to that described for other state-dependent sodiumchannel blockers (Cestéle, S., et al., op. cit.). These compounds mayalso be likely to interact with sites outside of the inner cavity andhave allosteric effects on sodium ion conduction through the channelpore.

Any of these consequences may ultimately be responsible for the overalltherapeutic benefit provided by these compounds.

Accordingly, the compounds of the invention are sodium channel blockersand are therefore useful for treating diseases and conditions inmammals, for example humans, and other organisms, including all thosediseases and conditions which are the result of aberrantvoltage-dependent sodium channel biological activity or which may beameliorated by modulation of voltage-dependent sodium channel biologicalactivity. In particular, the compounds of the invention, i.e., thecompounds of formula (I) and embodiments and (or stereoisomers,geometric isomers, tautomers, solvates, metabolites, isotopes,pharmaceutically acceptable salts, or prodrugs thereof), are useful fortreating diseases and conditions in mammals, for example humans, whichare the result of aberrant voltage-dependent NaV1.7 biological activityor which may be ameliorated by the modulation, preferably theinhibition, of NaV1.7 biological activity. In certain aspects, thecompounds of the invention selectively inhibit NaV1.7 over NaV1.5.

As defined herein, a sodium channel-mediated disease or condition refersto a disease or condition in a mammal, preferably a human, which isameliorated upon modulation of the sodium channel and includes, but isnot limited to, pain, central nervous conditions such as epilepsy,anxiety, depression and bipolar disease; cardiovascular conditions suchas arrhythmias, atrial fibrillation and ventricular fibrillation;neuromuscular conditions such as restless leg syndrome and muscleparalysis or tetanus; neuroprotection against stroke, neural trauma andmultiple sclerosis; and channelopathies such as erythromyalgia andfamilial rectal pain syndrome.

In one aspect, the present invention relates to compounds,pharmaceutical compositions and methods of using the compounds andpharmaceutical compositions for the treatment of sodium channel-mediateddiseases in mammals, preferably humans and preferably diseases andconditions related to pain, central nervous conditions such as epilepsy,anxiety, depression and bipolar disease; cardiovascular conditions suchas arrhythmias, atrial fibrillation and ventricular fibrillation;neuromuscular conditions such as restless leg syndrome and muscleparalysis or tetanus; neuroprotection against stroke, neural trauma andmultiple sclerosis; and channelopathies such as erythromyalgia andfamilial rectal pain syndrome, by administering to a mammal, for examplea human, in need of such treatment an effective amount of a sodiumchannel blocker modulating, especially inhibiting, agent.

A sodium channel-mediated disease or condition also includes painassociated with HIV, HIV treatment induced neuropathy, trigeminalneuralgia, glossopharyngeal neuralgia, neuropathy secondary tometastatic infiltration, adiposis dolorosa, thalamic lesions,hypertension, autoimmune disease, asthma, drug addiction (e.g., opiate,benzodiazepine, amphetamine, cocaine, alcohol, butane inhalation),Alzheimer, dementia, age-related memory impairment, Korsakoff syndrome,restenosis, urinary dysfunction, incontinence, Parkinson's disease,cerebrovascular ischemia, neurosis, gastrointestinal disease, sicklecell anemia, transplant rejection, heart failure, myocardial infarction,reperfusion injury, intermittant claudication, angina, convulsion,respiratory disorders, cerebral or myocardial ischemias, long-QTsyndrome, Catecholeminergic polymorphic ventricular tachycardia,ophthalmic diseases, spasticity, spastic paraplegia, myopathies,myasthenia gravis, paramyotonia congentia, hyperkalemic periodicparalysis, hypokalemic periodic paralysis, alopecia, anxiety disorders,psychotic disorders, mania, paranoia, seasonal affective disorder, panicdisorder, obsessive compulsive disorder (OCD), phobias, autism,Aspergers Syndrome, Retts syndrome, disintegrative disorder, attentiondeficit disorder, aggressivity, impulse control disorders, thrombosis,pre clampsia, congestive cardiac failure, cardiac arrest, Freidrich'sataxia, Spinocerebellear ataxia, myelopathy, radiculopathy, systemiclupus erythamatosis, granulomatous disease, olivo-ponto-cerebellaratrophy, spinocerebellar ataxia, episodic ataxia, myokymia, progressivepallidal atrophy, progressive supranuclear palsy and spasticity,traumatic brain injury, cerebral oedema, hydrocephalus injury, spinalcord injury, anorexia nervosa, bulimia, Prader-Willi syndrome, obesity,optic neuritis, cataract, retinal haemorrhage, ischaemic retinopathy,retinitis pigmentosa, acute and chronic glaucoma, macular degeneration,retinal artery occlusion, Chorea, Huntington's chorea, cerebral edema,proctitis, post-herpetic neuralgia, eudynia, heat sensitivity,sarcoidosis, irritable bowel syndrome, Tourette syndrome, Lesch-NyhanSyndrome, Brugado syndrome, Liddle syndrome, Crohns disease, multiplesclerosis and the pain associated with multiple sclerosis (MS),amyotrophic lateral sclerosis (ALS), disseminated sclerosis, diabeticneuropathy, peripheral neuropathy, charcot marie tooth syndrome,arthritic, rheumatoid arthritis, osteoarthritis, chondrocalcinosis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,myotonic dystrophy, muscular dystrophy, malignant hyperthermia, cysticfibrosis, pseudoaldosteronism, rhabdomyolysis, mental handicap,hypothyroidism, bipolar depression, anxiety, schizophrenia, sodiumchannel toxin related illnesses, familial erythromelalgia, primaryerythromelalgia, rectal pain, cancer, epilepsy, partial and generaltonic seizures, febrile seizures, absence seizures (petit mal),myoclonic seizures, atonic seizures, clonic seizures, Lennox Gastaut,West Syndome (infantile spasms), multiresistant seizures, seizureprophylaxis (anti-epileptogenic), familial Mediterranean fever syndrome,gout, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotectionunder ischaemic conditions caused by stroke or neural trauma,tachy-arrhythmias, atrial fibrillation and ventricular fibrillation andas a general or local anaesthetic.

As used herein, the term “pain” refers to all categories of pain and isrecognized to include, but is not limited to, neuropathic pain,inflammatory pain, nociceptive pain, idiopathic pain, neuralgic pain,orofacial pain, burn pain, burning mouth syndrome, somatic pain,visceral pain, myofacial pain, dental pain, cancer pain, chemotherapypain, trauma pain, surgical pain, post-surgical pain, childbirth pain,labor pain, chronic regional pain syndrome (CRPS), reflex sympatheticdystrophy, brachial plexus avulsion, neurogenic bladder, acute pain(e.g., musculoskeletal and post-operative pain), chronic pain,persistent pain, peripherally mediated pain, centrally mediated pain,chronic headache, migraine headache, familial hemiplegic migraine,conditions associated with cephalic pain, sinus headache, tensionheadache, phantom limb pain, peripheral nerve injury, pain followingstroke, thalamic lesions, radiculopathy, HIV pain, post-herpetic pain,non-cardiac chest pain, irritable bowel syndrome and pain associatedwith bowel disorders and dyspepsia, and combinations thereof.

Furthermore, sodium channel blockers have clinical uses in addition topain. The present invention therefore also relates to compounds,pharmaceutical compositions and methods of using the compounds andpharmaceutical compositions for the treatment of diseases or conditionssuch as cancer and pruritus (itch).

Pruritus, commonly known as itch, is a common dermatological condition.While the exact causes of pruritus are complex and incompletelyunderstood, there has long been evidence that itch involves sensoryneurons, especially C fibers, similar to those that mediate pain(Schmelz, M., et al., J. Neurosci. (1997), 17: 8003-8). In particular,it is believed that sodium influx through voltage-gated sodium channelsis essential for the propagation of itch sensation from the skin.Transmission of the itch impulses results in the unpleasant sensationthat elicits the desire or reflex to scratch.

Multiple causes and electrical pathways for eliciting itch are known. Inhumans, pruritis can be elicited by histamine or PAR-2 agonists such asmucunain that activate distinct populations of C fibers (Namer, B., etal., J. Neurophysiol. (2008), 100: 2062-9). A variety of neurotrophicpeptides are known to mediate itch in animal models (Wang, H., andYosipovitch, G., International Journal of Dermatology (2010), 49: 1-11).Itch can also be elicited by opioids, evidence of distinct pharmacologyfrom that of pain responses.

There exists a complex interaction between itch and pain responses thatarises in part from the overlapping sensory input from the skin (Ikoma,A., et al., Arch. Dermatol. (2003), 139: 1475-8) and also from thediverse etiology of both pain and pruritis. Pain responses canexacerbate itching by enhancing central sensitization or lead toinhibition of painful scratching. Particularly severe forms of chronicitch occur when pain responses are absent, as in the case ofpost-herpetic itch (Oaklander, A. L., et al., Pain (2002), 96: 9-12).

The compounds of the invention can also be useful for treating pruritus.The rationale for treating itch with inhibitors of voltage-gated sodiumchannels, especially NaV1.7, is as follows:

The propagation of electrical activity in the C fibers that sensepruritinergic stimulants requires sodium entry through voltage-gatedsodium channels.

NaV1.7 is expressed in the C fibers and kerotinocytes in human skin(Zhao, P., et al., Pain (2008), 139: 90-105).

A gain of function mutation of NaV1.7 (L858F) that causeserythromelalgia also causes chronic itch (Li, Y., et al., Clinical andExperimental Dermatology (2009), 34: e313-e4).

Chronic itch can be alleviated with treatment by sodium channelblockers, such as the local anesthetic lidocaine (Oaklander, A. L., etal., Pain (2002), 96: 9-12; Villamil, A. G., et al., The AmericanJournal of Medicine (2005), 118: 1160-3). In these reports, lidocainewas effective when administered either intravenously or topically (aLidoderm patch). Lidocaine can have multiple activities at the plasmaconcentrations achieved when administered systemically, but whenadministered topically, the plasma concentrations are only about 1 μM(Center for Drug Evaluation and Research NDA 20-612). At theseconcentrations, lidocaine is selective for sodium channel block andinhibits spontaneous electrical activity in C fibers and pain responsesin animal models (Xiao, W. H., and Bennett, G. J. Pain (2008), 137:218-28). The types of itch or skin irritation, include, but are notlimited to:

psoriatic pruritus, itch due to hemodyalisis, aguagenic pruritus, anditching caused by skin disorders (e.g., contact dermatitis), systemicdisorders, neuropathy, psychogenic factors or a mixture thereof;

itch caused by allergic reactions, insect bites, hypersensitivity (e.g.,dry skin, acne, eczema, psoriasis), inflammatory conditions or injury;

itch associated with vulvar vestibulitis; and

skin irritation or inflammatory effect from administration of anothertherapeutic such as, for example, antibiotics, antivirals andantihistamines.

The compounds of the invention are also useful in treating certaincancers, such as hormone sensitive cancers, such as prostate cancer(adenocarcinoma), breast cancer, ovarian cancer, testicular cancer andthyroid neoplasia, in a mammal, preferably a human. The voltage gatedsodium channels have been demonstrated to be expressed in prostate andbreast cancer cells. Up-regulation of neonatal NaV1.5 occurs as anintegral part of the metastatic process in human breast cancer and couldserve both as a novel marker of the metastatic phenotype and atherapeutic target (Clin. Cancer Res. (2005), August 1; 11(15): 5381-9).Functional expression of voltage-gated sodium channel alpha-subunits,specifically NaV1.7, is associated with strong metastatic potential inprostate cancer (CaP) in vitro. Voltage-gated sodium channelalpha-subunits immunostaining, using antibodies specific to the sodiumchannel alpha subunit was evident in prostatic tissues and markedlystronger in CaP vs non-CaP patients (Prostate Cancer Prostatic Dis.,2005; 8(3):266-73). See also Diss, J. K. J., et al., Mol. Cell.Neurosci. (2008), 37:537-547 and Kis-Toth, K., et al., The Journal ofImmunology (2011), 187:1273-1280.

In consideration of the above, in one embodiment, the present inventionprovides a method for treating a mammal for, or protecting a mammal fromdeveloping, a sodium channel-mediated disease, especially pain,comprising administering to the mammal, especially a human, in needthereof, a therapeutically effective amount of a compound of theinvention or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention wherein the compoundmodulates the activity of one or more voltage-dependent sodium channels.

In another embodiment of the invention is a method of treating a diseaseor a condition in a mammal, preferably a human, wherein the disease orcondition is selected from the group consisting of pain, depression,cardiovascular diseases, respiratory diseases, and psychiatric diseases,and combinations thereof, and wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount of anembodiment of a compound of the invention, as set forth above, as astereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

One embodiment of this embodiment is wherein the disease or condition isselected from the group consisting of neuropathic pain, inflammatorypain, visceral pain, cancer pain, chemotherapy pain, trauma pain,surgical pain, post surgical pain, childbirth pain, labor pain,neurogenic bladder, ulcerative colitis, chronic pain, persistent pain,peripherally mediated pain, centrally mediated pain, chronic headache,migraine headache, sinus headache, tension headache, phantom limb pain,peripheral nerve injury, and combinations thereof.

Another embodiment of this embodiment is wherein the disease orcondition is selected from the group consisting of pain associated withHIV, HIV treatment induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis, irritablebowel syndrome, Crohns disease, pain associated with multiple sclerosis(MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy,peripheral neuropathy, arthritic, rheumatoid arthritis, osteoarthritis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,malignant hyperthermia, cystic fibrosis, pseudoaldosteronism,rhabdomyolysis, hypothyroidism, bipolar depression, anxiety,schizophrenia, sodium channel toxin related illnesses, familialerythromelalgia, primary erythromelalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscaused by stroke or neural trauma, tachy arrhythmias, atrialfibrillation and ventricular fibrillation.

Another embodiment of the invention is a method of treating, but notpreventing, pain in a mammal, wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount of acompound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

One embodiment of this embodiment is a method wherein the pain isselected from the group consisting of neuropathic pain, inflammatorypain, visceral pain, cancer pain, chemotherapy pain, trauma pain,surgical pain, post surgical pain, childbirth pain, labor pain, dentalpain, chronic pain, persistent pain, peripherally mediated pain,centrally mediated pain, chronic headache, migraine headache, sinusheadache, tension headache, phantom limb pain, peripheral nerve injury,trigeminal neuralgia, post herpetic neuralgia, eudynia, familialerythromelalgia, primary erythromelalgia, familial rectal pain orfibromyalgia, and combinations thereof.

Another embodiment of this embodiment is a method wherein the pain isassociated with a disease or condition selected from HIV, HIV treatmentinduced neuropathy, heat sensitivity, tosarcoidosis, irritable bowelsyndrome, Crohns disease, multiple sclerosis, amyotrophic lateralsclerosis, diabetic neuropathy, peripheral neuropathy, rheumatoidarthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia,myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis,pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression,anxiety, schizophrenia, sodium channel toxin related illnesses,neurogenic bladder, ulcerative colitis, cancer, epilepsy, partial andgeneral tonic seizures, restless leg syndrome, arrhythmias, ischaemicconditions caused by stroke or neural trauma, tachy arrhythmias, atrialfibrillation and ventricular fibrillation.

Another embodiment of the invention is the method of treating pain in amammal, preferably a human, by the inhibition of ion flux through avoltage dependent sodium channel in the mammal, wherein the methodcomprises administering to the mammal in need thereof a therapeuticallyeffective amount of an embodiment of a compound of the invention, as setforth above, as a stereoisomer, enantiomer or tautomer thereof ormixtures thereof, or a pharmaceutically acceptable salt, solvate orprodrug thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention, as setforth above, as a stereoisomer, enantiomer or tautomer thereof ormixtures thereof, or a pharmaceutically acceptable salt, solvate orprodrug thereof, and a pharmaceutically acceptable excipient.

Another embodiment of the invention is the method of treating pruritusin a mammal, preferably a human, wherein the method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of an embodiment of a compound of the invention, as set forthabove, as a stereoisomer, enantiomer or tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention, as set forth above, asa stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

Another embodiment of the invention is the method of treating cancer ina mammal, preferably a human, wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount of anembodiment of a compound of the invention, as set forth above, as astereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

Another embodiment of the invention is the method of decreasing ion fluxthrough a voltage dependent sodium channel in a cell in a mammal,wherein the method comprises contacting the cell with an embodiment of acompound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof.

Another embodiment of the invention is the method of selectivelyinhibiting a first voltage-gated sodium channel over a secondvoltage-gated sodium channel in a mammal, wherein the method comprisesadministering to the mammal an inhibitory amount of a compound offormula (I), or an embodiment of a compound of formula (I).

Another embodiment of the invention is the method of selectivelyinhibiting NaV1.7 in a mammal or a mammalian cell as compared to NaV1.5,wherein the method comprises administering to the mammal in need thereofan inhibitory amount of a compound of formula (I) or an embodiment of anembodiment thereof.

For each of the above embodiments described related to treating diseasesand conditions in a mammal, the present invention also contemplatesrelatedly a compound of formula I or an embodiment thereof for the useas a medicament in the treatment of such diseases and conditions.

For each of the above embodiments described related to treating diseasesand conditions in a mammal, the present invention also contemplatesrelatedly the use of a compound of formula I or an embodiment thereoffor the manufacture of a medicament for the treatment of such diseasesand conditions.

Another embodiment of the invention is a method of using the compoundsof formula (I) as standards or controls in in vitro or in vivo assays indetermining the efficacy of test compounds in modulatingvoltage-dependent sodium channels.

In another embodiment of the invention, the compounds of formula (I) areisotopically-labeled by having one or more atoms therein replaced by anatom having a different atomic mass or mass number. Suchisotopically-labeled (i.e., radiolabelled) compounds of formula (I) areconsidered to be within the scope of this invention. Examples ofisotopes that can be incorporated into the compounds of formula (I)include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, chlorine, and iodine, such as, but not limited to, ²H,³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I,and ¹²⁵I, respectively. These isotopically-labeled compounds would beuseful to help determine or measure the effectiveness of the compounds,by characterizing, for example, the site or mode of action on the sodiumchannels, or binding affinity to pharmacologically important site ofaction on the sodium channels, particularly NaV1.7. Certainisotopically-labeled compounds of formula (I), for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e., 1⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof formula (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

Testing Compounds

The assessment of the compounds of the invention in mediating,especially inhibiting, the sodium channel ion flux can be determinedusing the assays described hereinbelow. Alternatively, the assessment ofthe compounds in treating conditions and diseases in humans may beestablished in industry standard animal models for demonstrating theefficacy of compounds in treating pain. Animal models of humanneuropathic pain conditions have been developed that result inreproducible sensory deficits (allodynia, hyperalgesia, and spontaneouspain) over a sustained period of time that can be evaluated by sensorytesting. By establishing the degree of mechanical, chemical, andtemperature induced allodynia and hyperalgesia present, severalphysiopathological conditions observed in humans can be modeled allowingthe evaluation of pharmacotherapies.

In rat models of peripheral nerve injury, ectopic activity in theinjured nerve corresponds to the behavioural signs of pain. In thesemodels, intravenous application of the sodium channel blocker and localanesthetic lidocaine can suppress the ectopic activity and reverse thetactile allodynia at concentrations that do not affect general behaviourand motor function (Mao, J. and Chen, L. L, Pain (2000), 87:7-17).Allometric scaling of the doses effective in these rat models,translates into doses similar to those shown to be efficacious in humans(Tanelian, D. L. and Brose, W. G., Anesthesiology (1991),74(5):949-951). Furthermore, Lidoderm®, lidocaine applied in the form ofa dermal patch, is currently an FDA approved treatment for post-herpeticneuralgia (Devers, A. and Glaler, B. S., Clin. J. Pain (2000),16(3):205-8).

The present invention readily affords many different means foridentification of sodium channel modulating agents that are useful astherapeutic agents. Identification of modulators of sodium channel canbe assessed using a variety of in vitro and in vivo assays, e.g.,measuring current, measuring membrane potential, measuring ion flux,(e.g., sodium or guanidinium), measuring sodium concentration, measuringsecond messengers and transcription levels, and using e.g.,voltage-sensitive dyes, radioactive tracers, and patch-clampelectrophysiology.

One such protocol involves the screening of chemical agents for abilityto modulate the activity of a sodium channel thereby identifying it as amodulating agent.

A typical assay described in Bean et al., J. General Physiology (1983),83:613-642, and Leuwer, M., et al., Br. J. Pharmacol (2004),141(1):47-54, uses patch-clamp techniques to study the behaviour ofchannels. Such techniques are known to those skilled in the art, and maybe developed, using current technologies, into low or medium throughputassays for evaluating compounds for their ability to modulate sodiumchannel behaviour.

Throughput of test compounds is an important consideration in the choiceof screening assay to be used. In some strategies, where hundreds ofthousands of compounds are to be tested, it is not desirable to use lowthroughput means. In other cases, however, low throughput issatisfactory to identify important differences between a limited numberof compounds. Often it will be necessary to combine assay types toidentify specific sodium channel modulating compounds.

Electrophysiological assays using patch clamp techniques is accepted asa gold standard for detailed characterization of sodium channel compoundinteractions, and as described in Bean et al., op. cit. and Leuwer, M.,et al., op. cit. There is a manual low-throughput screening (LTS) methodwhich can compare 2-10 compounds per day; a recently developed systemfor automated medium-throughput screening (MTS) at 20-50 patches (i.e.compounds) per day; and a technology from Molecular Devices Corporation(Sunnyvale, Calif.) which permits automated high-throughput screening(HTS) at 1000-3000 patches (i.e. compounds) per day.

One automated patch-clamp system utilizes planar electrode technology toaccelerate the rate of drug discovery. Planar electrodes are capable ofachieving high-resistance, cells-attached seals followed by stable,low-noise whole-cell recordings that are comparable to conventionalrecordings. A suitable instrument is the PatchXpress 7000A (AxonInstruments Inc, Union City, Calif.). A variety of cell lines andculture techniques, which include adherent cells as well as cellsgrowing spontaneously in suspension are ranked for seal success rate andstability. Immortalized cells (e.g. HEK and CHO) stably expressing highlevels of the relevant sodium ion channel can be adapted intohigh-density suspension cultures.

Other assays can be selected which allow the investigator to identifycompounds which block specific states of the channel, such as the openstate, closed state or the resting state, or which block transition fromopen to closed, closed to resting or resting to open. Those skilled inthe art are generally familiar with such assays.

Binding assays are also available. Designs include traditionalradioactive filter based binding assays or the confocal basedfluorescent system available from Evotec OAI group of companies(Hamburg, Germany), both of which are HTS.

Radioactive flux assays can also be used. In this assay, channels arestimulated to open with veratridine or aconitine and held in astabilized open state with a toxin, and channel blockers are identifiedby their ability to prevent ion influx. The assay can use radioactive22[Na] and 14[C] guanidinium ions as tracers. FlashPlate & Cytostar-Tplates in living cells avoids separation steps and are suitable for HTS.Scintillation plate technology has also advanced this method to HTSsuitability. Because of the functional aspects of the assay, theinformation content is reasonably good.

Yet another format measures the redistribution of membrane potentialusing the FLIPR system membrane potential kit (HTS) available fromMolecular Dynamics (a division of Amersham Biosciences, Piscataway,N.J.). This method is limited to slow membrane potential changes. Someproblems may result from the fluorescent background of compounds. Testcompounds may also directly influence the fluidity of the cell membraneand lead to an increase in intracellular dye concentrations. Still,because of the functional aspects of the assay, the information contentis reasonably good.

Sodium dyes can be used to measure the rate or amount of sodium ioninflux through a channel. This type of assay provides a very highinformation content regarding potential channel blockers. The assay isfunctional and would measure Na+ influx directly. CoroNa Red, SBFIand/or sodium green (Molecular Probes, Inc. Eugene Oreg.) can be used tomeasure Na influx; all are Na responsive dyes. They can be used incombination with the FLIPR instrument. The use of these dyes in a screenhas not been previously described in the literature. Calcium dyes mayalso have potential in this format.

In another assay, FRET based voltage sensors are used to measure theability of a test compound to directly block Na influx. Commerciallyavailable HTS systems include the VIPR™ II FRET system (LifeTechnologies, or Aurora Biosciences Corporation, San Diego, Calif., adivision of Vertex Pharmaceuticals, Inc.) which may be used inconjunction with FRET dyes, also available from Aurora Biosciences. Thisassay measures sub-second responses to voltage changes. There is norequirement for a modifier of channel function. The assay measuresdepolarization and hyperpolarizations, and provides ratiometric outputsfor quantification. A somewhat less expensive MTS version of this assayemploys the FLEXstation™ (Molecular Devices Corporation) in conjunctionwith FRET dyes from Aurora Biosciences. Other methods of testing thecompounds disclosed herein are also readily known and available to thoseskilled in the art.

Modulating agents so identified are then tested in a variety of in vivomodels so as to determine if they alleviate pain, especially chronicpain or other conditions such as cancer and pruritus (itch) with minimaladverse events. The assays described below in the Biological AssaysSection are useful in assessing the biological activity of the instantcompounds.

Typically, the efficacy of a compound of the invention is expressed byits IC50 value (“Inhibitory Concentration—50%”), which is the measure ofthe amount of compound required to achieve 50% inhibition of theactivity of the target sodium channel over a specific time period. Forexample, representative compounds of the present invention havedemonstrated IC50's ranging from less than 100 nanomolar to less than 10micromolar in the patch voltage clamp NaV1.7 electrophysiology assaydescribed herein.

In another aspect of the invention, the compounds of the invention canbe used in in vitro or in vivo studies as exemplary agents forcomparative purposes to find other compounds also useful in treatmentof, or protection from, the various diseases disclosed herein.

Another aspect of the invention relates to inhibiting NaV1.1, NaV1.2,NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 activity,preferably NaV1.7 activity, in a biological sample or a mammal,preferably a human, which method comprises administering to the mammal,preferably a human, or contacting said biological sample with a compoundof formula (I) or a pharmaceutical composition comprising a compound offormula (I). The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,NaV1.8, or NaV1.9 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumion channels in biological and pathological phenomena; and thecomparative evaluation of new sodium ion channel inhibitors.

The compounds of the invention (or stereoisomers, geometric isomers,tautomers, solvates, metabolites, isotopes, pharmaceutically acceptablesalts, or prodrugs thereof) and/or the pharmaceutical compositionsdescribed herein which comprise a pharmaceutically acceptable excipientand one or more compounds of the invention, can be used in thepreparation of a medicament for the treatment of sodium channel-mediateddisease or condition in a mammal.

Combination Therapy

The compounds of the invention may be usefully combined with one or moreother compounds of the invention or one or more other therapeutic agentor as any combination thereof, in the treatment of sodiumchannel-mediated diseases and conditions. For example, a compound of theinvention may be administered simultaneously, sequentially or separatelyin combination with other therapeutic agents, including, but not limitedto:

opiates analgesics, e.g., morphine, heroin, cocaine, oxymorphine,levorphanol, levallorphan, oxycodone, codeine, dihydrocodeine,propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone,meripidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine,butorphanol, nalbuphine and pentazocine;

non-opiate analgesics, e.g., acetomeniphen, salicylates (e.g., aspirin);

nonsteroidal antiinflammatory drugs (NSAIDs), e.g., ibuprofen, naproxen,fenoprofen, ketoprofen, celecoxib, diclofenac, diflusinal, etodolac,fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin,ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam,nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetinand zomepirac;

anticonvulsants, e.g., carbamazepine, oxcarbazepine, lamotrigine,valproate, topiramate, gabapentin and pregabalin;

antidepressants such as tricyclic antidepressants, e.g., amitriptyline,clomipramine, despramine, imipramine and nortriptyline;

COX-2 selective inhibitors, e.g., celecoxib, rofecoxib, parecoxib,valdecoxib, deracoxib, etoricoxib, and lumiracoxib;

alpha-adrenergics, e.g., doxazosin, tamsulosin, clonidine, guanfacine,dexmetatomidine, modafinil, and 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;

barbiturate sedatives, e.g., amobarbital, aprobarbital, butabarbital,butabital, mephobarbital, metharbital, methohexital, pentobarbital,phenobartital, secobarbital, talbutal, theamylal and thiopental;

tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1antagonist, e.g., (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione(TAK-637),5-[[2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one(MK-869), aprepitant, lanepitant, dapitant or3-[[2-methoxy5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S);

coal-tar analgesics, in particular paracetamol;

serotonin reuptake inhibitors, e.g., paroxetine, sertraline,norfluoxetine (fluoxetine desmethyl metabolite), metabolitedemethylsertraline, ′3 fluvoxamine, paroxetine, citalopram, citaloprammetabolite desmethylcitalopram, escitalopram, d,l-fenfluramine,femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine,nefazodone, cericlamine, trazodone and fluoxetine;

noradrenaline (norepinephrine) reuptake inhibitors, e.g., maprotiline,lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine,mianserin, buproprion, buproprion metabolite hydroxybuproprion,nomifensine and viloxazine (Vivalan®)), especially a selectivenoradrenaline reuptake inhibitor such as reboxetine, in particular(S,S)-reboxetine, and venlafaxine duloxetine neurolepticssedative/anxiolytics;

dual serotonin-noradrenaline reuptake inhibitors, such as venlafaxine,venlafaxine metabolite O-desmethylvenlafaxine, clomipramine,clomipramine metabolite desmethylclomipramine, duloxetine, milnacipranand imipramine;

acetylcholinesterase inhibitors such as donepezil;

5-HT3 antagonists such as ondansetron;

metabotropic glutamate receptor (mGluR) antagonists;

local anaesthetic such as mexiletine and lidocaine;

corticosteroid such as dexamethasone;

antiarrhythimics, e.g., mexiletine and phenytoin;

muscarinic antagonists, e.g., tolterodine, propiverine, tropsium tchloride, darifenacin, solifenacin, temiverine and ipratropium;

cannabinoids;

vanilloid receptor agonists (e.g., resinferatoxin) or antagonists (e.g.,capsazepine);

sedatives, e.g., glutethimide, meprobamate, methaqualone, anddichloralphenazone;

anxiolytics such as benzodiazepines,

antidepressants such as mirtazapine,

topical agents (e.g., lidocaine, capsacin and resiniferotoxin);

muscle relaxants such as benzodiazepines, baclofen, carisoprodol,chlorzoxazone, cyclobenzaprine, methocarbamol and orphrenadine;

anti-histamines or H1 antagonists;

NMDA receptor antagonists;

5-HT receptor agonists/antagonists;

PDEV inhibitors;

Tramadol®;

cholinergic (nicotinc) analgesics;

alpha-2-delta ligands;

prostaglandin E2 subtype antagonists;

leukotriene B4 antagonists;

5-lipoxygenase inhibitors; and

5-HT3 antagonists.

Sodium channel-mediated diseases and conditions that may be treatedand/or prevented using such combinations include but not limited to,pain, central and peripherally mediated, acute, chronic, neuropathic aswell as other diseases with associated pain and other central nervousdisorders such as epilepsy, anxiety, depression and bipolar disease; orcardiovascular disorders such as arrhythmias, atrial fibrillation andventricular fibrillation; neuromuscular disorders such as restless legsyndrome and muscle paralysis or tetanus; neuroprotection againststroke, neural trauma and multiple sclerosis; and channelopathies suchas erythromyalgia and familial rectal pain syndrome.

As used herein “combination” refers to any mixture or permutation of oneor more compounds of the invention and one or more other compounds ofthe invention or one or more additional therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include simultaneous orsequentially delivery of a compound of the invention with one or moretherapeutic agents. Unless the context makes clear otherwise,“combination” may include dosage forms of a compound of the inventionwith another therapeutic agent. Unless the context makes clearotherwise, “combination” may include routes of administration of acompound of the invention with another therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include formulations ofa compound of the invention with another therapeutic agent. Dosageforms, routes of administration and pharmaceutical compositions include,but are not limited to, those described herein.

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

EXAMPLES

These examples serve to provide guidance to a skilled artisan to prepareand use the compounds, compositions and methods of the invention. Whileparticular embodiment of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinventions.

The chemical reactions in the examples described can be readily adaptedto prepare a number of other compounds of the invention, and alternativemethods for preparing the compounds of this invention are deemed to bewithin the scope of this invention. For example, the synthesis ofnon-examplified compounds according to the invention can be successfullyperformed by modifications apparent to those skilled in the art, forexample, by appropriately protecting interferring group, by utilizingother suitable reagents known in the art, for example, by appropriatelyprotecting interferring groups by utilizing other suitable reagentsknown in the art other than those described, and/or by making routinemodifications of reaction conditions.

In the examples below, unless otherwise indicated all temperatures areset forth in degrees Celcius. Commerically available reagents werepurchased from suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge and were used without further purification unlessotherwise indicated. The reactions set forth below were done generallyunder a positive pressure of nitrogen or argon or with a drying tube(unless otherwise stated) in anhydrous solvents, and the reaction flaskswere typically fitted with rubber septa for the introduction ofsubstrates and reagents via syringe. Glassware was oven dried and/orheat dried. ¹H NMR spectra were obtained in deuterated CDCl₃, d₆-DMSO,CH₃OD or d₆-acetone solvent solutions (reported in ppm) using ortrimethylsilane (TMS) or residual non-deuterated solvent peaks as thereference standard. When peak multiplicities are reported, the followingabbreviates are used: s (singlet), d (doublet), t (triplet), q(quartet), m (multiplet, br (broadened), dd (doublet of doublets), dt(doublet of triplets). Coupling constants, when given, ar reported in Hz(Hertz).

All abbreviations used to describe reagents, reaction conditions orequipment are intended to be consistent with the definitions set forthin the “List of standard abbreviates and acronyms”.

The chemical names of discrete compounds of the invention were obtainedusing the structure naming feature of ChemDraw naming program.

Abbreviations

MeCN Acetonitrile

EtOAc Ethyl acetate

DCE Dichloroethane

DCM Dichloromethane

DIPEA Diisopropylethylamine

DEA Diethylamine

DMAP 4-dimethylaminopyridine

DMF N,N-Dimethylformamide

DMSO Dimethyl sulfoxide

FA Formic acid

IPA Isopropyl alcohol

TFA Trifluoroacetic acid

EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

HCl Hydrochloric acid

HPLC High Pressure Liquid Chromatography

LCMS Liquid Chromatography Mass Spectrometry

MeOH Methanol

NMP N-methyl-2-pyrrolidone

RPHPLC Reverse phase high pressure liquid chromatography

RT Retention time

THF Tetrahydrofuran

Example 1 Synthesis of4-((adamantan-1-yl)methoxy)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide

Step 1: Preparation of N-(tert-butyldiethylsilyl)cyclopropanesulfonamide

A mixture of cyclopropanesulfonamide (10.0 g, 82.5 mmol) andtriethylamine (23.0 mL, 165 mmol) in anhydrous tetrahydrofuran (120 mL)under a nitrogen atmosphere was treated withtert-butylchlorodimethylsilane (14.3 g, 94.9 mmol). The mixture wasstirred for 48 h and then diluted with diethyl ether (150 mL) andfiltered. The filtrate was concentrated in vacuo and the residue wastriturated with diethyl ether (100 mL). The solid was filtered and thefiltrate was concentrated in vacuo to provide the title compound as abeige solid (17.7 g, 94% yield): ¹H NMR (300 MHz, CDCl₃) δ 4.42 (s, 1H),2.52-2.44 (m, 1H), 1.22-1.13 (m, 2H), 1.06-1.03 (m, 2H), 0.95 (s, 9H),0.29 (s, 6H).

Step 2: Preparation ofN-(tert-butyldimethylsilyl)cyclopropanesulfonimidamide

A mixture of triphenylphosphine (7.90 g, 30.0 mmol) and anhydrouschloroform (30 mL) was treated with hexachloroethane (7.10, 30.0 mmol)under a nitrogen atmosphere. The mixture was heated to 70° C. for 18 h,then cooled to ambient temperature and treated with triethylamine (5.60mL, 40.5 mmol). The mixture was stirred for 20 minutes, cooled to 0° C.,and treated with N-(tert-butyldimethylsilyl)cyclopropanesulfonamide(6.38 g, 27.0 mmol). The resulting mixture was stirred for 30 minutes,after which gaseous ammonia was bubbled through for 7 minutes. Theresulting mixture was stirred at 0° C. for 30 minutes and then warmed toambient temperature for 1 h. The reaction mixture was filtered and thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography, eluting with a gradient of 0 to 60% ethyl acetate inhexanes to provide the title compound as a colorless solid (4.79 g, 75%yield): ¹H NMR (300 MHz, CDCl₃) δ 4.35 (s, 2H), 2.62-2.53 (m, 1H),1.15-1.01 (m, 2H), 0.99-0.88 (m, 11H), 0.12 (s, 3H), 0.11 (s, 3H); MS(ES+) m/z: 235.4 (M+1).

Step 3: Preparation of Cyclopropanesulfonimidamide Hydrochloride

A mixture of N-(tert-butyldimethylsilyl)cyclopropanesulfonimidamide(3.79 g, 16.1 mmol) in formic acid (50 mL) and water (6 mL) was stirredat ambient temperature for 1 h and then concentrated in vacuo. Theresidue was triturated with diethyl ether (50 mL) and filtered. Thesolid was co-evaporated with 3M hydrochloric acid (3×30 mL) to providethe title compound as an off white solid (2.40 g, 96% yield): ¹H NMR(300 MHz, DMSO-d₆) δ 8.99 (s, 3H), 3.16-3.08 (m, 1H), 1.23 (d, J=6.3 Hz,4H); MS (ES+) m/z: 121.1 (M+1).

Step 4: Preparation of4-((adamantan-1-yl)methoxy)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide

A mixture of 4-((-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid (prepared according to WO 2013177224, 0.50 g, 1.45 mmol) andcarbonyl diimidazole (0.47 g, 2.90 mmol) in anhydrous tetrahydrofuran(20 mL) was refluxed under a nitrogen atmosphere for 30 minutes. Thereaction mixture was cooled to ambient temperature and treated withcyclopropanesulfonimidamide hydrochloride (0.45 g, 2.90 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.87 mL, 5.80 mmol). The resultingmixture was stirred for 45 minutes and then quenched with water (20 mL).The mixture was extracted with ethyl acetate (100 mL) and the organiclayer was washed with saturated aqueous ammonium chloride (2×50 mL),brine (50 mL), and dried over anhydrous sodium sulfate. The mixture wasfiltered and the filtrate was concentrated in vacuo. The residue waspurified by column chromatography (R_(f)=0.2 in 1:1 hexanes:ethylacetate) to provide the title compound as a colorless solid (0.25 g,39%): ¹H NMR (300 MHz, DMSO-d₆) δ 9.92 (br s, 1H), 8.44 (s, 1H),7.76-7.62 (m, 5H), 7.37 (d, J=8.9 Hz, 1H), 5.56 (br s, 1H), 4.54-4.43(m, 1H), 4.30 (s, 2H), 3.46-2.74 (m, 4H), 2.21-2.06 (m, 1H), 1.99-1.81(m, 1H), 1.04 (br s, 6H); MS (ES+) m/z: 447.2 (M+1).

Example 2 Synthesis of4-((4-chloro-2-cyanophenoxy)methyl)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide

Step 1: Preparation of tert-butyl4-((4-chloro-2-cyanophenoxy)methyl)-5-cyclopropyl-2-fluorobenzoate

A mixture of tert-butyl5-cyclopropyl-2-fluoro-4-(((methylsulfonyl)oxy)methyl)benzoate (preparedaccording to WO 201578374, 0.30 g, 0.88 mmol),5-chloro-2-hydroxybenzonitrile (0.14 g, 0.93 mmol) and potassiumcarbonate (0.18 g, 1.32 mmol) in N,N-dimethylformamide (2.9 mL) wasstirred under a nitrogen atmosphere for 22 h. The mixture was dilutedwith ethyl acetate (35 mL), washed with brine (5×20 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo toprovide the title compound as a tan solid (0.36 g, quant. yield): ¹H NMR(300 MHz, CDCl₃) δ 7.64-7.55 (m, 2H), 7.52-7.45 (m, 1H), 7.26-7.21 (m,1H), 6.96-6.88 (m, 1H), 5.39 (s, 2H), 1.90-1.81 (m, 1H), 1.61 (s, 9H),1.04-0.96 (m, 2H), 0.76-0.69 (m, 2H).

Step 2: Preparation of4-((4-chloro-2-cyanophenoxy)methyl)-5-cyclopropyl-2-fluorobenzoic acid

A solution of tert-butyl4-((4-chloro-2-cyanophenoxy)methyl)-5-cyclopropyl-2-fluorobenzoate (0.36g, 0.88 mmol) in dichloromethane (6.0 mL) was treated withtrifluoroacetic acid (0.8 mL). The reaction mixture was stirred for 3.5h and then concentrated in vacuo to provide the title compound as a tansolid (0.30 g, quant. yield): ¹H NMR (300 MHz, CDCl₃+10% CD₃OD) δ7.73-7.68 (m, 1H), 7.60-7.57 (m, 1H), 7.52-7.46 (m, 1H), 7.31-7.30 (m,1H), 6.96-6.91 (m, 1H), 5.37 (s, 2H), 1.88-1.81 (m, 1H), 1.02-0.96 (m,2H), 0.74-0.70 (m, 2H) (Note: exchangeable protons not observed).

Step 3: Preparation of4-((4-chloro-2-cyanophenoxy)methyl)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 1, step 4 and makingnon-critical variations as required to replace4-((-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-((4-chloro-2-cyanophenoxy)methyl)-5-cyclopropyl-2-fluorobenzoic acid,the title compound was obtained as a colorless solid (0.03 g, 13%yield): ¹H NMR (300 MHz, DMSO-d₆) δ 7.94 (d, J=2.6 Hz, 1H), 7.74 (dd,J=9.1, 2.6 Hz, 1H), 7.45 (d, J=7.5 Hz, 1H), 7.41 (d, J=9.2 Hz, 1H), 7.33(br s, 2H), 7.27 (d, J=11.5 Hz, 1H), 5.43 (s, 2H), 3.08-2.97 (m, 1H),2.04-1.90 (m, 1H), 1.21-0.97 (m, 4H), 0.94-0.87 (m, 2H), 0.66-0.57 (m,2H); MS (ES+) m/z: 448.1, 450.1 (M+1).

Example 3 Synthesis ofN-(cyclopropanesulfonimidoyl)-5-cyclopropyl-4-((3,5-dichlorophenoxy)methyl)-2-fluorobenzamide

Following the procedure as described in Example 1, step 4 and makingnon-critical variations as required to replace4-((-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-((3,5-dichlorophenoxy)methyl)-2-fluorobenzoic acid(prepared according to WO 2014008458), the title compound was obtainedas a colorless solid (0.22 g, 32% yield): ¹H NMR (300 MHz, CDCl₃+10%CD₃OD) δ 7.61 (d, J=7.3 Hz, 1H), 7.09 (d, J=11.7 Hz, 1H), 6.93-6.88 (m,1H), 6.79 (d, J=1.8 Hz, 2H), 5.12 (s, 2H), 3.00-2.89 (m, 1H), 1.80-1.68(m, 1H), 1.32-1.23 (m, 2H), 1.09-1.00 (m, 2H), 0.93-0.84 (m, 2H),0.67-0.59 (m, 2H) (Note: Exchangeable protons not observed); MS (ES+)m/z: 457.1, 459.1 (M+1).

Example 4 Synthesis of4-((adamantan-1-yl)methoxy)-5-chloro-N-(cyclopropanesulfonimidoyl)-2-fluorobenzamide

Following the procedure as described in Example 1, step 4 and makingnon-critical variations as required to replace4-((-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-((adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoic acid (preparedaccording to WO 2013177224), the title compound was obtained as acolorless solid (0.065 g, 29% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 7.85(d, J=7.9 Hz, 1H), 7.31 (br s, 2H), 7.03 (d, J=12.7 Hz, 1H). 3.65 (s,2H), 3.07-2.96 (m, 1H), 1.99-1.90 (m, 3H), 1.74-1.55 (m, 12H), 1.21-0.93(m, 4H); MS (ES+) m/z: 441.2, 443.1 (M+1).

Example 5 Synthesis ofN-(cyclopropanesulfonimidoyl)-5-cyclopropyl-4-((3,4-dimethylphenoxy)methyl)-2-fluorobenzamide

Step 1: Preparation of tert-butyl5-cyclopropyl-4-((3,4-dimethylphenoxy)methyl)-2-fluorobenzoate

Following the procedure as described in Example 2, step 1 and makingnon-critical variations as required to replace5-chloro-2-hydroxybenzonitrile with 3,4-dimethylphenol, the titlecompound was obtained as a colorless solid (0.50 g, 88% yield): ¹H NMR(300 MHz, CDCl₃) δ 7.58 (d, J=6.9 Hz, 1H), 7.27 (d, J=11.5 Hz, 1H), 7.06(d, J=8.4 Hz, 1H), 6.81 (d, J=2.6 Hz, 1H), 6.74 (dd, J=8.2, 2.7 Hz, 1H),5.22 (s, 2H), 2.26 (s, 3H), 2.22 (s, 3H), 1.92-1.82 (m, 1H), 1.61 (s,9H), 1.02-0.95 (m, 2H), 0.75-0.70 (m, 2H).

Step 2: Preparation ofN-(cyclopropanesulfonimidoyl)-5-cyclopropyl-4-((3,4-dimethyl-phenoxy)methyl)-2-fluorobenzamide

A solution of tert-butyl5-cyclopropyl-4-((3,4-dimethylphenoxy)methyl)-2-fluorobenzoate (0.50 g,1.29 mmol) in dichloromethane (5 mL) was treated with trifluoroaceticacid (1.0 mL), stirred for 72 h, and then concentrated in vacuo. Theresidue dissolved in anhydrous tetrahydrofuran (20 mL), treated withcarbonyl diimidazole (0.49 g, 3.00 mmol), and refluxed under a nitrogenatmosphere for 30 minutes. The reaction mixture was cooled to ambienttemperature and treated with cyclopropanesulfonimidamide hydrochloride(0.47 g, 3.00 mmol) and 1,8-diazabicyclo-[5.4.0]undec-7-ene (1.20 mL,8.00 mmol). The resulting mixture was stirred for 18 h and then quenchedwith water (20 mL). The mixture was extracted with ethyl acetate (80 mL)and the organic layer was washed with saturated aqueous ammoniumchloride (2×80 mL), brine (50 mL), and dried over anhydrous sodiumsulfate. The mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by column chromatography (R_(f)=0.2 in1:1 hexanes:ethyl acetate) to provide the title compound as a colorlesssolid (0.15 g, 24% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=7.5 Hz,1H), 7.23 (d, J=12.0 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.79-6.75 (m, 1H),6.68 (dd, J=8.3, 2.6 Hz, 1H), 5.97 (br s, 2H), 5.18 (s, 2H), 3.08-2.98(m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.88-1.77 (m, 1H), 1.40-1.33 (m,2H), 1.15-1.06 (m, 2H), 0.97-0.88 (m, 2H), 0.74-0.64 (m, 2H); MS (ES+)m/z: 417.2 (M+1).

Example 6 Synthesis of4-((adamantan-1-yl)methoxy)-5-chloro-2-fluoro-N—(S-methylsulfonimidoyl)-benzamide

Step 1: Preparation of N-(tert-butyldimethylsilyl)methanesulfonamide

Following the procedure as described in Example 1, step 1 and makingnon-critical variations as required to replace cyclopropanesulfonamidewith methanesulfonamide, the title compound was obtained as a colorlesssolid (12.54 g, 93% yield): ¹H NMR (300 MHz, CDCl₃) δ 4.94 (s, 1H), 3.02(s, 3H), 0.95 (s, 9H), 0.30 (s, 6H).

Step 2: Preparation of N-(tert-butyldimethylsilyl)methanesulfonimidamide

Following the procedure as described in Example 1, step 2 and makingnon-critical variations as required to replaceN-(tert-butyldimethylsilyl)cyclopropanesulfonamide withN-(tert-butyldimethylsilyl)methanesulfonamide, the title compound wasobtained as a colorless solid (8.37 g, 67% yield): ¹H NMR (300 MHz,CDCl₃) δ 4.69 (s, 2H), 3.13 (s, 3H), 0.91 (s, 9H, 0.13 (s, 3H), 0.11 (s,3H); MS (ES+) m/z: 209.2 (M+1).

Step 3: Preparation of Methanesulfonimidamide Hydrochloride

Following the procedure as described in Example 1, step 3 and makingnon-critical variations as required to replaceN-(tert-butyldimethylsilyl)cyclopropanesulfonimidamide withN-(tert-butyldimethylsilyl)methanesulfonimidamide, the title compoundwas obtained as a colorless solid (4.92 g, 98% yield): ¹H NMR (300 MHz,DMSO-d₆) δ 9.01 (s, 3H), 3.50 (s, 3H).

Step 4: Preparation of4-((adamantan-1-yl)methoxy)-5-chloro-2-fluoro-N—(S-methyl-sulfonimidoyl)benzamide

Following the procedure as described in Example 1, step 4 and makingnon-critical variations as required to replace4-((-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-((adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoic acid andcyclopropanesulfonimidamide hydrochloride with methanesulfonimidamidehydrochloride, the title compound was obtained as a colorless solid(0.50 g, 40% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (d, J=7.9 Hz, 1H),7.03 (d, J=12.7 Hz, 1H), 3.65 (s, 2H), 3.31 (s, 3H), 3.28 (s, 2H),1.98-1.91 (m, 3H), 1.73-1.56 (m, 12H); MS (ES+) m/z: 415.2, 417.2 (M+1).

Example 7 Synthesis of4-((adamantan-1-yl)methoxy)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 1, step 4 and makingnon-critical variations as required to replacecyclopropanesulfonimidamide hydrochloride with methanesulfonimidamidehydrochloride, the title compound was obtained as a colorless solid(0.35 g, 48% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.55 (d, J=8.9 Hz, 1H),6.49 (d, J=13.4 Hz, 1H), 5.78 (s, 2H), 3.50 (s, 2H), 3.35 (s, 3H),2.06-1.95 (m, 4H), 1.81-1.62 (m, 12H), 0.91-0.83 (m, 2H), 0.67-0.58 (m,2H); MS (ES+) m/z: 421.2 (M+1).

Example 8 Synthesis of4-(3-chloro-4-(trifluoromethoxy)phenoxy)-N-(cyclopropanesulfonimidoyl)-2,5-difluorobenzamide

Step 1: Preparation ofN-(tert-butyldimethylsilyl)-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-N-(cyclopropanesulfonimidoyl)-2,5-difluorobenzamide

To a solution of4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2,5-difluorobenzoic acid(prepared according to WO20120077883A1, 0.36 g, 0.98 mmol) in anhydroustetrahydrofuran (10 mL) was added carbonyl diimidazole (0.32 g, 2.00mmol). The solution was heated to reflux under a nitrogen atmosphere for1 h, then cooled to ambient temperature. To this was addedN-(tert-butyldimethylsilyl)cyclopropanesulfonimidamide (0.45 g, 1.94mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.59 mL, 3.9 mmol). Thesolution was stirred at ambient temperature for 15 h, then concentratedin vacuo. The residue was purified by column chromatography, elutingwith a gradient of 0-20% ethyl acetate in hexanes to afford the titlecompound as a colorless syrup (0.17 g, 30% yield): ¹H NMR (300 MHz,CDCl₃) δ 7.94 (dd, J=6.9, 10.8 Hz, 1H), 7.35 (dd, J=1.1, 9.0 Hz, 1H),7.16 (d. J=2.9 Hz, 1H), 6.98 (dd, J=2.9, 9.0 Hz, 1H). 6.81 (dd, J=6.3,11.1 Hz, 1H), 3.06-2.97 (m, 1H), 1.36-1.25 (m, 3H), 1.11-1.07 (m, 2H),0.97 (s, 9H), 0.28 (s, 6H); MS (ES+) m/z: 585.1, 587.1 (M+1).

Step 2. Preparation of4-(3-chloro-4-(trifluoromethoxy)phenoxy)-N-(cyclopropanesulfonimidoyl)-2,5-difluorobenzamide

To a solution ofN-(tert-butyldimethylsilyl)-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-N-(cyclopropanesulfonimidoyl)-2,5-difluorobenzamide(0.17 g, 0.29 mmol) in acetonitrile (5 mL) was added formic acid (0.33mL, 8.7 mmol) and water (0.32 mL, 18 mmol). The solution was stirred atambient temperature for 1 h and was then concentrated in vacuo. Theresidue was purified by column chromatography, eluting with a 0-70%gradient of ethyl acetate in hexanes to afford the title compound as acolorless syrup (0.12 g, 90% yield): ¹H NMR (300 MHz, CDCl₃) δ 8 7.89(dd, J=6.9, 10.9 Hz, 1H), 7.31 (d, J=9.0 Hz, 1H), 7.12 (d, J=2.8 Hz,1H), 6.94 (dd, J=2.9, 9.0 Hz, 1H), 6.76 (dd, J=6.4, 10.7 Hz, 1H), 5.82(s, 2H), 3.06-2.97 (m, 1H), 1.41-1.37 (m, 2H), 1.20-1.13 (m, 2H); ¹⁹FNMR (282 MHz, CDCl₃) δ −58.1 (s, 3F), −112.4 (d, J=16.4 Hz, 1F), −135.4,(d, J=16.4 Hz, 1F); MS (ES+) m/z 470.9, 472.9 (M+1).

Example 9 Synthesis of5-chloro-4-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluorobenzamide

Step 1. Preparation ofN-(tert-butyldimethylsilyl)-5-chloro-4-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluorobenzamide

Following the procedure as described in Example 8, Step 1 and makingnon-critical variations as required to replace4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2,5-difluorobenzoic acid with5-chloro-4-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)-2-fluorobenzoicacid (prepared according to WO2014008458), the title compound wasobtained as a colorless syrup (0.27 g, 38% yield): ¹H NMR (300 MHz,CDCl₃) δ 8.22 (d, J=7.7 Hz, 1H), 7.90 (d, J=2.6 Hz, 1H), 7.50 (d, J=2.5Hz, 1H), 6.61 (d, J=11.5 Hz, 1H), 6.10 (tt, J=4.8, 53.1 Hz, 1H), 4.79(t, J=12.2 Hz, 2H), 3.05-2.96 (m, 1H), 1.35-1.25 (m, 3H), 1.10-1.06 (m,2H), 0.97 (s, 9H), 0.29 (s, 6H); ¹⁹F NMR (282 MHz, CDCl₃) δ −109.1 (s,1F), −124.8 (s, 2F), −139.0 (s, 2F); MS (ES+) m/z 648.1, 650.1 (M+1).

Step 2. Preparation of5-chloro-4-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluorobenzamide

Following the procedure as described in Example 8, step 2 and makingnon-critical variations as required to replaceN-(tert-butyldimethylsilyl)-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-N-(cyclopropanesulfonimidoyl)-2,5-difluorobenzamidewithN-(tert-butyldimethylsilyl)-5-chloro-4-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluorobenzamide,the title compound was obtained as a colorless solid (0.18 g, 80%yield): ¹H NMR (300 MHz, CDCl₃) δ 8.17 (d, J=7.6 Hz, 1H), 7.87 (d, J=2.6Hz, 1H), 7.47 (d, J=2.6 Hz, 1H), 6.56 (d, J=11.2 Hz, 1H), 6.07 (dt,J=4.8, 53.1 Hz, 1H), 5.82 (br s, 2H), 4.75 (t, J=12.2 Hz, 2H), 3.06-2.97(m, 1H), 1.40-1.36 (m, 2H), 1.20-1.14 (m, 2H); 19F NMR (282 MHz, CDCl₃)δ −108.4 (s, 1F), −124.8 (s, 2F), −139.0 (s, 2F); MS (ES+) m/z 533.9,535.9 (M+1).

Example 10 Synthesis of4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide

Step 1. Preparation ofN-(tert-butyldimethylsilyl)-4-((3-chloro-5-(trifluoromethoxy)-phenoxy)methyl)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 8, Step 1 and makingnon-critical variations as required to replace4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2,5-difluorobenzoic acid with4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluorobenzoicacid (prepared according to WO2014008458), the title compound wasobtained as a colorless syrup (0.021 g, 11% yield): ¹H NMR (300 MHz,CDCl₃) δ 7.80 (d, J=7.6 Hz, 1H), 7.27 (d, J=12.4 Hz, 1H), 6.95-6.91 (m,2H), 6.77 (br s, 1H), 5.26 (s, 2H), 3.09-3.01 (m, 1H), 1.90-1.80 (m,1H), 1.35-1.26 (m, 3H), 1.07-1.01 (m, 4H), 0.95 (s, 9H), 0.79-0.74 (m,2H), 0.21 (s, 6H); MS (ES+) m/z 621.1, 623.1 (M+1).

Step 2. Preparation of4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 8, step 2 and makingnon-critical variations as required to replaceN-(tert-butyldimethylsilyl)-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-N-(cyclopropanesulfonimidoyl)-2,5-difluorobenzamidewithN-(tert-butyldimethylsilyl)-4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide,the title compound was obtained as a colorless solid (0.017 g, quant.yield): ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d, J=7.5 Hz, 1H), 7.19 (d,J=11.6 Hz, 1H), 6.90-6.87 (m, 2H), 6.73 (br s, 1H), 5.80 (br s, 2H),5.21 (s, 2H), 3.08-3.00 (m, 1H), 1.86-1.76 (m, 1H), 1.41-1.36 (m, 2H),1.17-1.13 (m, 2H), 0.99-0.93 (m, 2H), 0.73-0.69 (m, 2H); ¹⁹F NMR (282MHz, CDCl₃) δ −57.8 (s, 3F), −114.7 (s, 1F); MS (ES+) m/z 507.0, 509.0(M+1).

Example 11 Synthesis ofN-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluoro-4-((3-fluoro-5-(trifluoromethyl)phenoxy)methyl)benzamide

Step 1. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((3-fluoro-5-(trifluoromethyl)phenoxy)methyl)benzoate

Following the procedure as described in Example 2, step 1 and makingnon-critical variations as required to replace5-chloro-2-hydroxybenzonitrile with 3-fluoro-5-(trifluoromethyl)phenol,the title compound was obtained following purification by columnchromatography (eluting with a 0-10% gradient of ethyl acetate inhexanes) as a colorless syrup (0.64 g, 79% yield): MS (ES+) m/z 429.1(M+1).

Step 2. Preparation of5-cyclopropyl-2-fluoro-4-((3-fluoro-5-(trifluoromethyl)-phenoxy)methyl)benzoicacid

Following the procedure as described in Example 2, step 2 and makingnon-critical variations as required to replace tert-butyl4-((4-chloro-2-cyanophenoxy)methyl)-5-cyclopropyl-2-fluorobenzoate withtert-butyl5-cyclopropyl-2-fluoro-4-((3-fluoro-5-(trifluoromethyl)phenoxy)methyl)benzoate,the title compound was obtained as a colorless solid (0.56 g, quant.yield): MS (ES−) m/z 371.1 (M−1).

Step 3. Preparation ofN-(tert-butyldimethylsilyl)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluoro-4-((3-fluoro-5-(trifluoromethyl)phenoxy)methyl)benzamide

Following the procedure as described in Example 8, Step 1 and makingnon-critical variations as required to replace4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2,5-difluorobenzoic acid with5-cyclopropyl-2-fluoro-4-((3-fluoro-5-(trifluoromethyl)phenoxy)methyl)benzoicacid, the title compound was obtained as a colorless syrup (0.015 g, 8%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J=7.5 Hz, 1H), 7.28 (d,J=12.4 Hz, 1H), 7.06 (br s, 1H), 7.02-6.99 (m, 1H), 6.88 (dt, J=2.1,10.1 Hz, 1H), 5.30 (s, 2H), 3.09-3.01 (m, 1H), 1.91-1.82 (m, 1H),1.35-1.27 (m, 3H), 1.08-1.01 (m, 2H), 0.95 (s, 9H), 0.79-0.75 (m, 2H),0.21 (s, 6H); MS (ES+) m/z 589.2 (M+1).

Step 4. Preparation ofN-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluoro-4-((3-fluoro-5-(trifluoromethyl)phenoxy)methyl)benzamide

Following the procedure as described in Example 8, step 2 and makingnon-critical variations as required to replaceN-(tert-butyldimethylsilyl)-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-N-(cyclopropanesulfonimidoyl)-2,5-difluorobenzamidewithN-(tert-butyldimethylsilyl)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluoro-4-((3-fluoro-5-(trifluoromethyl)phenoxy)methyl)benzamide, the title compound was obtained as a colorless solid(0.009 g, 76% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d, J=7.4 Hz, 1H),7.20 (d, J=11.7 Hz, 1H), 7.02 (br s, 1H), 6.97-6.94 (m, 1H), 6.84 (dt,J=2.1, 10.2 Hz, 1H), 5.83 (br s, 2H), 5.25 (s, 2H), 3.08-3.00 (m, 1H),1.87-1.78 (m, 1H), 1.41-1.37 (m, 2H), 1.18-1.11 (m, 2H), 1.00-0.93 (m,2H), 0.74-0.69 (m, 2H); ¹⁹F NMR (282 MHz, CDCl₃) δ −62.9 (s, 3F), −108.5(s, 1F), −114.7 (s, 1F); MS (ES+) m/z 475.1 (M+1).

Example 12 Synthesis ofN-(azetidine-1-sulfonimidoyl)-5-chloro-4-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy-2-fluorobenzamide

Step 1. Preparation ofN-(tert-butyldimethylsilyl)azetidine-1-sulfonimidamide

Following the procedures as described in Example 1, steps 1 and 2 andmaking non-critical variations as required to replacecyclopropanesulfonamide with azetidine-1-sulfonamide, the title compoundwas obtained as a colorless solid (7.36 g, 30% yield): ¹H NMR (300 MHz,DMSO-d₆) δ 6.20 (s, 2H), 3.57 (t, J=7.6 Hz, 4H), 2.01-1.91 (m, 2H), 0.84(s, 9H), 0.00 (s, 3H), −0.01 (s, 3H); MS (ES+) m/z 250.2 (M+1).

Step 2. Preparation ofN-(azetidine-1-sulfonimidoyl)-N-(tert-butyldimethylsilyl)-5-chloro-4-((5-chloro-6-2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)-2-fluorobenzamide

Following the procedure as described in Example 8, Step 1 and makingnon-critical variations as required to replace4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2,5-difluorobenzoic acid with5-chloro-4-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)-2-fluorobenzoicacid and N-(tert-butyldimethylsilyl)cyclopropanesulfonimidamide withN-(tert-butyldimethylsilyl)-azetidine-1-sulfonimidamide, the titlecompound was obtained as a colorless syrup (0.12 g, 23% yield): ¹H NMR(300 MHz, CDCl₃) δ 8.21 (d, J=7.6 Hz, 1H), 7.90 (d, J=2.6 Hz, 1H), 7.50(d, J=2.6 Hz, 1H), 6.62 (d, J=11.2 Hz, 1H), 6.10 (tt, J=4.8, 53.1 Hz,1H), 4.79 (t, J=12.2 Hz, 2H), 4.01-3.87 (m, 4H), 2.28-2.17 (m, 2H), 1.28(br s, 1H), 0.99 (s, 9H), 0.36 (s, 3H), 0.33 (s, 3H); MS (ES+) m/z663.1, 665.1 (M+1).

Step 3. Preparation ofN-(azetidine-1-sulfonimidoyl)-5-chloro-4-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)-2-fluorobenzamide

Following the procedure as described in Example 8, step 2 and makingnon-critical variations as required to replaceN-(tert-butyldimethylsilyl)-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-N-(cyclopropanesulfonimidoyl)-2,5-difluorobenzamidewithN-(azetidine-1-sulfonimidoyl)-N-(tert-butyldimethylsilyl)-5-chloro-4-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)-2-fluorobenzamide,the title compound was obtained as a colorless solid (0.095 g, 84%yield): ¹H NMR (300 MHz, CDCl₃) δ 8.14 (d, J=7.6 Hz, 1H), 7.86 (d, J=2.6Hz, 1H), 7.47 (d, J=2.6 Hz, 1H), 6.56 (d, J=11.1 Hz, 1H), 6.06 (tt,J=4.8, 53.1 Hz, 1H), 5.78 (br s, 2H), 4.75 (t, J=12.2 Hz, 2H), 4.00 (t,J=7.8 Hz, 4H), 2.31-2.21 (m, 2H); 19F NMR (282 MHz, CDCl₃) δ −108.3 (s,1F), −124.8 (t, J=4.5 Hz, 2F), −139.0 (t, J=4.5 Hz, 2F); MS (ES+) m/z549.0, 551.0 (M+1).

Example 13 Synthesis of4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-N-(azetidine-1-sulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide

Step 1. Preparation of4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-N-(azetidine-1-sulfonimidoyl)-N-(tert-butyldimethylsilyl)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 8, Step 1 and makingnon-critical variations as required to replace4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2,5-difluorobenzoic acid with4-((-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid andN-(tert-butyldimethyl-silyl)cyclopropanesulfonimidamide withN-(tert-butyldimethylsilyl)azetidine-1-sulfonimidamide, the titlecompound was obtained as a colorless syrup (0.13 g, 16% yield): ¹H NMR(300 MHz, CDCl₃) δ 7.61 (d, J=8.9 Hz, 1H), 6.55 (d, J=13.6 Hz, 1H),4.04-3.93 (m, 4H), 3.55 (s, 2H), 2.21-2.10 (m, 2H), 2.06-2.01 (m, 3H),1.82-1.70 (m, 13H). 0.95 (s, 9H), 0.71-0.67 (m, 2H), 0.21 (s, 6H); MS(ES+) m/z 576.2 (M+1).

Step 2. Preparation of4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-N-(azetidine-1-sulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 8, step 2 and makingnon-critical variations as required to replaceN-(tert-butyldimethylsilyl)-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-N-(cyclopropanesulfonimidoyl)-2,5-difluorobenzamidewith4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-N-(azetidine-1-sulfonimidoyl)-N-(tert-butyldimethylsilyl)-5-cyclopropyl-2-fluorobenzamide,the title compound was obtained as a colorless solid (0.051 g, 48%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.56 (d, J=8.8 Hz, 1H), 6.49 (d,J=13.2 Hz, 1H), 3.97 (t, J=7.8 Hz, 4H), 3.50 (s, 2H), 2.27-2.16 (m, 2H),2.07-2.00 (m, 4H), 1.78-1.66 (m, 12H), 0.89-0.86 (m, 2H), 0.65-0.61 (m,2H) (Note: exchangeable protons not observed); ¹⁹F NMR (282 MHz, CDCl₃)δ −110.8 (s, 1F); MS (ES+) m/z 462.1 (M+1).

Example 14 Synthesis of5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluorobenzamide

Step 1. Preparation ofN-(tert-butyldimethylsilyl)-5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluorobenzamide

Following the procedure as described in Example 8, Step 1 and makingnon-critical variations as required to replace4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2,5-difluorobenzoic acid with5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoicacid, the title compound was obtained as a colorless solid (0.20 g, 54%yield): ¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, J=7.5 Hz, 1H), 7.90 (d, J=2.8Hz, 1H), 7.52-7.50 (m, 1H), 6.61 (d, J=11.6 Hz, 1H), 4.84 (q, J=8.5 Hz,2H), 3.05-2.95 (m, 1H), 1.57 (s, 9H), 1.09 (br s, 1H), 0.98 (s, 6H),0.36-0.25 (m, 4H); MS (ES+) m/z 616.1, 618.1 (M+1).

Step 2. Preparation of5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluorobenzamide

Following the procedure as described in Example 8, step 2 and makingnon-critical variations as required to replaceN-(tert-butyldimethylsilyl)-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-N-(cyclopropanesulfonimidoyl)-2,5-difluorobenzamidewithN-(tert-butyldimethylsilyl)-5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluorobenzamide,the title compound was obtained as a colorless solid (0.13 g, 81%yield): ¹H NMR (300 MHz, CDCl₃) δ 8.19 (d, J=7.6 Hz, 1H), 7.88 (d, J=2.6Hz, 1H), 7.50 (d, J=2.6 Hz, 1H), 6.59 (d, J=11.2 Hz, 1H), 5.81 (br s,2H), 4.82 (q, J=8.4 Hz, 2H), 3.07-2.99 (m, 1H), 1.43-1.38 (m, 2H),1.20-1.16 (m, 2H); ¹⁹F NMR (282 MHz, CDCl₃) δ −73.7 (s, 3F), −108.4 (s,1F); MS (ES+) m/z 501.9, 503.9 (M+1).

Example 15 Synthesis of4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluoro-5-(2-methoxypyridin-3-yl)benzamide

Step 1. Preparation of methyl4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoate

To a mixture of methyl4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluoro-5-iodobenzoate(prepared according to WO2014008458A2, 2.10 g, 4.61 mmol) and(2-methoxypyridin-3-yl)boronic acid (1.03 g, 6.76 mmol) in1,2-dimethoxyethane (48 mL) was addedtetrakis(triphenylphosphine)palladium(0) (0.53 g, 0.46 mmol) and 2 Maqueous sodium carbonate (9.2 mL, 18.4 mmol). The mixture was heated toreflux under a nitrogen atmosphere for 8 h, then cooled to ambienttemperature and concentrated in vacuo. The residue was diluted withethyl acetate (50 mL), washed with brine (3×25 mL), dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The residue waspurified by column chromatography, eluting with a 0-20% gradient ofethyl acetate in hexanes to afford the title compound as an orange foamysolid (1.13 g, 55% yield): ¹H NMR (300 MHz, CDCl₃) δ 8.22 (dd, J=1.9,5.0 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.85 (d, J=2.6 Hz, 1H), 7.59 (dd,J=1.8, 7.2 Hz, 1H), 7.42 (d, J=2.6 Hz, 1H), 7.00 (dd, J=5.0, 7.2 Hz,1H), 6.59 (d, J=11.7 Hz, 1H), 5.38-5.25 (m, 1H), 3.94 (s, 3H), 3.92 (s,3H), 1.41 (d, J=6.2 Hz, 6H); MS (ES+) m/z 447.0, 449.0 (M+1).

Step 2. Preparation of4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoicacid

To a solution of methyl4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoate(1.13 g, 2.53 mmol) in tetrahydrofuran (20 mL) was added water (7 mL)and lithium hydroxide (0.60 g, 25.1 mmol). The mixture was heated toreflux for 3 h, then cooled to ambient temperature, diluted with 1 Mhydrochloric acid (150 mL), and extracted with ethyl acetate (2×150 mL).The combined organic layers were dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo to afford the title compound as acolorless foamy solid (1.12 g, quant. yield): MS (ES+) m/z 433.0, 434.9(M+1).

Step 3. Preparation ofN-(tert-butyldimethylsilyl)-4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluoro-5-(7-methoxypyridin-3-yl)benzamide

Following the procedure as described in Example 8, Step 1 and makingnon-critical variations as required to replace4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2,5-difluorobenzoic acid with4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoicacid, the title compound was obtained as a colorless solid (0.14 g, 30%yield): ¹H NMR (300 MHz, CDCl₃) δ 8.21 (dd, J=1.9, 5.1 Hz, 1H), 8.08 (d,J=8.7 Hz, 1H), 7.84 (d, J=2.7 Hz, 1H), 7.60 (dd, J=1.9, 7.2 Hz, 1H),7.41 (d, J=2.6 Hz, 1H), 7.00 (dd, J=5.0, 7.2 Hz, 1H), 6.59 (d, J=12.6Hz, 1H), 5.36-5.28 (m, 1H), 3.91 (s, 3H), 3.08-2.99 (m, 1H), 1.66-1.54(m, 3H), 1.42 (d, J=6.2 Hz, 6H), 0.95 (s, 9H), 0.24 (s, 6H); MS (ES+)m/z 649.2, 651.2 (M+1).

Step 4. Preparation of4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluoro-5-(2-methoxypyridin-3-yl)benzamide

Following the procedure as described in Example 8, step 2 and makingnon-critical variations as required to replaceN-(tert-butyldimethylsilyl)-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-N-(cyclopropanesulfonimidoyl)-2,5-difluorobenzamidewithN-(tert-butyldimethylsilyl)-4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluoro-5-(2-methoxypyridin-3-yl)benzamide,the title compound was obtained as a colorless solid (0.099 g, 88%yield): ¹H NMR (300 MHz, CDCl₃) δ 8.20 (d, J=4.8 Hz, 1H), 8.05 (d, J=8.5Hz, 1H), 7.82 (d, J=2.6 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.39 (d, J=2.6Hz, 1H), 7.00-6.96 (m, 1H), 6.56 (d, J=12.0 Hz, 1H), 5.83 (br s, 2H),5.33-5.25 (m, 1H), 3.90 (s, 3H), 3.09-3.00 (m, 1H), 1.40-1.38 (m, 8H),1.16-1.14 (m, 2H); MS (ES+) m/z 535.0, 537.0 (M+1).

Example 16 Synthesis of5-chloro-4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluorobenzamide

Step 1. Preparation of tert-butyl5-chloro-4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluorobenzoate

To a solution of tert-butyl 5-chloro-2,4-difluorobenzoate (preparedaccording to International Patent Application Publication NumberWO2012007883A1, 6.63 g, 26.7 mmol) and 5-chloro-6-isopropoxypyridin-3-ol(5.00 g, 26.7 mmol) in anhydrous N,N-dimethylformamide (100 mL) wasadded potassium carbonate (7.39 g, 53.5 mmol). The mixture was stirredat ambient temperature for 18 h, then diluted with diethyl ether (200mL), washed with saturated aqueous sodium bicarbonate (2×200 mL), driedover anhydrous sodium sulfate, filtered, and concentrated in vacuo toafford the title compound as a colorless solid (5.30 g, 48% yield): ¹HNMR (300 MHz, CDCl₃) δ 7.56 (d, J=7.4 Hz, 1H), 7.47 (d, J=2.7 Hz, 1H),7.01 (d, J=2.7 Hz, 1H), 6.12 (d, J=11.1 Hz, 1H), 4.97-4.85 (m, 1H), 1.17(s, 9H), 0.99 (d, J=6.2 Hz, 6H).

Step 2. Preparation of5-chloro-4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluorobenzoic acid

Following the procedure as described in Example 2, step 2 and makingnon-critical variations as required to replace tert-butyl4-((4-chloro-2-cyanophenoxy)methyl)-5-cyclopropyl-2-fluorobenzoate withtert-butyl5-chloro-4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluorobenzoate,the title compound was obtained as a colorless solid (2.12 g, 82%yield): ¹H NMR (300 MHz, DMSO-d₆) δ 13.48 (br s, 1H), 8.15 (d, J=2.7 Hz,1H), 8.06-8.03 (m, 2H), 7.07 (d, J=11.6 Hz, 1H), 5.40-5.28 (m, 1H), 1.40(d, J=6.2 Hz, 6H).

Step 3. Preparation ofN-(tert-butyldimethylsilyl)-5-chloro-4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluorobenzamide

Following the procedure as described in Example 8, Step 1 and makingnon-critical variations as required to replace4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2,5-difluorobenzoic acid with5-chloro-4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluorobenzoicacid, the title compound was obtained as a colorless solid (0.11 g, 18%yield): ¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, J=8.0 Hz, 1H), 7.91 (d, J=2.7Hz, 1H), 7.45 (d, J=2.7 Hz, 1H), 6.56 (d, J=11.8 Hz, 1H), 5.39-5.31 (m,1H), 3.05-2.96 (m, 1H), 1.63-1.53 (m, 3H), 1.43 (d, J=6.2 Hz, 6H),1.11-1.06 (m, 2H), 0.96 (s, 9H), 0.27 (s, 6H); MS (ES+) m/z 462.0, 464.0(M+1).

Step 4. Preparation of5-chloro-4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluorobenzamide

Following the procedure as described in Example 8, step 2 and makingnon-critical variations as required to replaceN-(tert-butyldimethylsilyl)-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-N-(cyclopropanesulfonimidoyl)-2,5-difluorobenzamidewithN-(tert-butyldimethylsilyl)-5-chloro-4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-N-(cyclopropanesulfonimidoyl)-2-fluorobenzamide,the title compound was obtained as a colorless solid (0.062 g, 69%yield): ¹H NMR (300 MHz, CDCl₃) δ 8.18 (d, J=7.7 Hz, 1H), 7.89 (d, J=2.6Hz, 1H), 7.43 (d, J=2.6 Hz, 1H), 6.53 (d, J=11.5 Hz, 1H), 5.81 (br s,2H), 5.37-5.27 (m, 1H), 3.08-2.99 (m, 1H), 1.42-1.38 (m, 8H), 1.21-1.14(m, 2H); MS (ES+) m/z 461.9, 463.9 (M+1).

Example 17 Synthesis ofN-(cyclopropanesulfonimidoyl)-5-cyclopropyl-4-(((R)-1-(2,6-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorobenzamide

Step 1. Preparation of tert-butyl(R)-5-cyclopropyl-4-((1-(2,6-dichlorobenzyl)-piperidin-3-yl)oxy)-2-fluorobenzoate

To a solution of tert-butyl(R)-5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate (preparedaccording to WO2015078374, 2.20 g, 6.56 mmol) and2,6-dichlorobenzaldehyde (1.58 g, 9.03 mmol) in anhydrous1,2-dichloroethane (50 mL) was added sodium triacetoxyborohydride (2.54g, 12.0 mmol). The solution was stirred at ambient temperature for 16 h,then diluted with 1 M hydrochloric acid (100 mL) and extracted withethyl acetate (3×100 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by column chromatography, eluting with a 0-10%gradient of diethyl ether in hexanes to afford the title compound as alight yellow syrup (0.92 g, 28% yield): ¹H NMR (300 MHz, CDCl₃) δ7.37-7.28 (m, 3H), 7.18-7.12 (m, 1H), 6.52 (d, J=12.8 Hz, 1H), 4.38-4.30(m, 1H), 3.85-3.74 (m, 2H), 3.12-3.08 (m, 1H), 2.77-2.72 (m, 1H),2.54-2.48 (m, 1H), 2.40-2.33 (m, 1H), 2.10-2.01 (m, 2H), 1.86-1.75 (m,1H), 1.63-1.54 (m, 11H), 0.92-0.87 (m, 2H), 0.66-0.62 (m, 2H); MS (ES+)m/z 494.0, 496.0 (M+1).

Step 2. Preparation of(R)-5-cyclopropyl-4-((1-(2,6-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorobenzoicacid

Following the procedure as described in Example 2, step 2 and makingnon-critical variations as required to replace tert-butyl4-((4-chloro-2-cyanophenoxy)methyl)-5-cyclopropyl-2-fluorobenzoate withtert-butyl(R)-5-cyclopropyl-4-((1-(2,6-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorobenzoate,the title compound was obtained as a colorless syrup as atrifluoroacetate salt (1.00 g, quant. yield): ¹H NMR (300 MHz, CDCl₃) δ10.00 (br s. 2H), 7.55-7.39 (m, 4H), 6.75 (d, J=11.5 Hz, 1H), 4.94-4.66(m, 3H), 4.20-4.13 (m, 1H), 3.84-3.78 (m, 1H), 3.26-3.05 (m, 2H),2.38-1.81 (m, 5H), 0.95-0.91 (m, 2H), 0.69-0.63 (m, 2H).

Step 3. Preparation ofN-(tert-butyldimethylsilyl)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-4-(((R)-1-(2,6-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorobenzamide

Following the procedure as described in Example 8, Step 1 and makingnon-critical variations as required to replace4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2,5-difluorobenzoic acid with(R)-5-cyclopropyl-4-((1-(2,6-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorobenzoicacid, the title compound was obtained as a colorless solid (0.16 g, 42%yield): ¹H NMR (300 MHz, CDCl₃) δ 8.52-8.48 (m, 1H), 7.55 (d, J=9.3 Hz,1H), 7.33-7.30 (m, 1H), 7.20-7.12 (m, 1H), 6.54 (d, J=14.7 Hz, 1H), 4.35(br s, 1H), 3.86-3.75 (m, 2H), 3.11-3.04 (m, 2H), 2.79-2.72 (m, 1H),2.57-2.50 (m, 1H), 2.44-2.35 (m, 1H), 2.10-2.02 (m, 2H), 1.87-1.79 (m,1H), 1.64-1.55 (m, 4H), 1.32-1.24 (m, 3H), 1.03-0.98 (m, 2H), 0.93 (s,9H), 0.71-0.63 (m, 2H), 0.15 (s, 6H); MS (ES+) m/z 654.2, 656.2 (M+1).

Step 4. Preparation ofN-(cyclopropanesulfonimidoyl)-5-cyclopropyl-4-(((R)-1-(2,6-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorobenzamide

Following the procedure as described in Example 8, step 2 and makingnon-critical variations as required to replaceN-(tert-butyldimethylsilyl)-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-N-(cyclopropanesulfonimidoyl)-2,5-difluorobenzamidewithN-(tert-butyldimethylsilyl)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-4-(((R)-1-(2,6-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorobenzamide,the title compound was obtained as a colorless solid (0.090 g, 70%yield): ¹H NMR (300 MHz, DMSO-d₆) δ 7.45-7.43 (m, 2H), 7.33-7.26 (m,4H). 6.78 (d, J=13.2 Hz, 1H), 4.49-4.42 (m, 1H), 3.75-3.66 (m, 2H),3.08-2.99 (m, 1H), 2.89-2.85 (m, 1H), 2.60-2.55 (m, 1H), 2.42-2.34 (m,1H), 2.08-1.88 (m, 2H), 1.77-1.66 (m, 1H), 1.55-1.47 (m, 2H), 1.23-0.99(m, 5H), 0.90-0.80 (m, 2H), 0.60-0.50 (m, 2H); MS (ES+) m/z 540.0, 542.0(M+1).

Example 18 Synthesis of 4-(((3r, 5r,7r)-adamantan-1-yl)methoxy)-N-(cyclopropanesulfonimidoyl)-2-fluoro-5-methoxybenzamide

Step 1. Preparation of tert-butyl4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-2-fluoro-5-hydroxybenzoate

To a solution of tert-butyl4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoate(prepared according to WO2013177224, 5.40 g, 13.7 mmol) in triethylamine(40 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.25 g, 0.55mmol Pd), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos, 0.90g, 2.19 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.0 mL, 27mmol) while degassing with argon. The solution was heated to refluxunder an argon atmosphere for 1.5 h, then cooled to 0° C. and quenchedwith water (10 mL). The mixture was filtered through a pad ofdiatomaceous earth that was washed with ethyl acetate (200 mL). Thefiltrate was concentrated in vacuo and the residue was partiallypurified by column chromatography, eluting with a 0-10% gradient ofethyl acetate in hexanes. The crude product was dissolved intetrahydrofuran (125 mL) and treated with 30% hydrogen peroxide (23 mL,230 mmol) and 1 M aqueous sodium hydroxide (23 mL, 23 mmol). Afterstirring for 1.5 h at ambient temperature, the mixture was quenched with1 M hydrochloric acid (200 mL) and extracted with ethyl acetate (2×250mL). The combined organic layers were dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. The residue was purifiedby column chromatography, eluting with a 0-10% gradient of ethyl acetatein hexanes to afford the title compound as a colorless solid (2.42 g,47% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.41 (d, J=7.2 Hz, 1H), 6.61 (d,J=11.8 Hz, 1H), 5.35 (s, 1H), 3.61 (s, 2H), 2.06 (br s, 3H), 1.82-1.64(m, 12H), 1.59 (s, 9H); MS (ES−) m/z 375.3 (M−1).

Step 2. Preparation of tert-butyl4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-2-fluoro-5-methoxybenzoate

To a solution of tert-butyl4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-2-fluoro-5-hydroxybenzoate (0.87g, 2.31 mmol) in anhydrous N,N-dimethylformamide (5 mL) was addedpotassium carbonate (0.64 g, 4.61 mmol) and iodomethane (0.29 mL, 4.6mmol). The mixture was stirred at ambient temperature under a nitrogenatmosphere for 1.5 h, then diluted with ethyl acetate (100 mL), washedwith brine (2×100 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. The residue was purified by columnchromatography, eluting with a 0-10% gradient of ethyl acetate inhexanes to afford the title compound as a colorless solid (0.75 g, 83%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.35 (d, J=7.1 Hz, 1H), 6.59 (d,J=12.3 Hz, 1H), 3.88 (s, 3H), 3.55 (s, 2H), 2.04 (br s, 3H), 1.81-1.64(m, 12H), 1.60 (s, 9H); MS (ES+) m/z 391.2 (M+1).

Step 3. Preparation of4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-2-fluoro-5-methoxybenzoic acid

Following the procedure as described in Example 2, step 2 and makingnon-critical variations as required to replace tert-butyl4-((4-chloro-2-cyanophenoxy)methyl)-5-cyclopropyl-2-fluorobenzoate withtert-butyl4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-2-fluoro-5-methoxybenzoate, thetitle compound was obtained as a colorless syrup (0.64 g, quant. yield):¹H NMR (300 MHz, DMSO-d₆) δ 12.91 (br s, 1H), 7.30 (d, J=7.2 Hz, 1H),6.95 (d, J=12.7 Hz, 1H), 3.79 (s, 3H), 3.61 (s, 2H), 1.98 (br s, 3H),1.74-1.58 (m, 12H); MS (ES+) m/z 335.1 (M+1).

Step 4. Preparation of4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-N-(tert-butyldimethylsilyl)-N-(cyclopropanesulfonimidoyl)-2-fluoro-5-methoxybenzamide

Following the procedure as described in Example 8, Step 1 and makingnon-critical variations as required to replace4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2,5-difluorobenzoic acid with4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-2-fluoro-5-methoxybenzoic acid,the title compound was obtained as a colorless solid (0.16 g, 48%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.53 (d, J=7.8 Hz, 1H), 6.63 (d,J=13.6 Hz, 1H), 3.89 (s, 3H), 3.57 (s, 2H), 2.06 (br s, 3H), 1.82-1.67(m, 12H), 1.56-1.54 (m, 1H), 1.33-1.27 (m, 2H), 1.05-1.02 (m, 2H), 0.93(s, 9H), 0.15 (s, 6H); MS (ES+) m/z 551.1 (M+1).

Step 5. Preparation of 4-(((3r, 5r.7r)-adamantan-1-yl)methoxy)-N-(cyclopropanesulfonimidoyl)-2-fluoro-5-methoxybenzamide

Following the procedure as described in Example 8, step 2 and makingnon-critical variations as required to replaceN-(tert-butyldimethylsilyl)-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-N-(cyclopropanesulfonimidoyl)-2,5-difluorobenzamidewith4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-N-(tert-butyldimethylsilyl)-N-(cyclopropanesulfonimidoyl)-2-fluoro-5-methoxybenzamide,the title compound was obtained as a colorless solid (0.093 g, 70%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.51 (d, J=7.4 Hz, 1H), 6.60 (d,J=12.7 Hz, 1H), 5.75 (br s, 2H), 3.86 (s, 3H), 3.54 (s, 2H), 3.11-3.03(m, 1H), 2.02-2.01 (m, 3H), 1.78-1.67 (m, 12H), 1.41-1.36 (m, 2H),1.18-1.10 (m, 2H); MS (ES+) m/z 437.1 (M+1).

Example 19 Synthesis of4-((1-(3-chloro-2-fluoro-6-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide

Step 1. Preparation ofN-(tert-butyldimethylsilyl)-4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide

To a solution of4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid (prepared according to WO2015078374, 0.60 g, 1.15 mmol) inanhydrous dichloromethane (2.5 mL) was added thionyl chloride (2.5 mL).The solution was stirred under a nitrogen atmosphere at ambienttemperature for 18 h and was then concentrated in vacuo. The residue wasdissolved in anhydrous dichloromethane (6 mL) and cooled to 0° C. Tothis solution was addedN-(tert-butyldimethylsilyl)cyclopropanesulfonimidamide (0.32 g, 1.38mmol) and triethylamine (0.35 mL, 2.5 mmol). The reaction was stirredunder a nitrogen atmosphere at ambient temperature for 20 h and was thendiluted with saturated aqueous ammonium chloride (50 mL) and extractedwith dichloromethane (3×50 mL). The combined organic extracts were driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo.The residue was purified by column chromatography, eluting with a 0-25%gradient of ethyl acetate in hexanes to afford the title compound as acolorless solid (0.15 g, 18% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.67-7.61(m, 3H), 6.57 (d, J=13.6 Hz, 1H), 4.04 (d, J=17.8 Hz, 2H), 3.70 (s, 2H),3.09-3.00 (m, 1H), 2.81-2.75 (m, 2H), 2.61-2.47 (m, 3H), 2.12-1.97 (m,4H), 1.93-1.81 (m, 1H), 1.32-1.25 (m, 3H), 1.14-1.01 (m, 3H), 0.93 (s,9H), 0.72-0.67 (m, 2H), 0.17 (s, 6H).

Step 2. Preparation of4-((1-(3-chloro-2-fluoro-6-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide

A solution ofN-(tert-butyldimethylsilyl)-4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)-benzyl)-4-fluoropiperidin-4-yl)methoxy)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamide(0.15 g, 0.20 mmol) in formic acid (0.23 mL) and water (0.22 mL) wasstirred at ambient temperature for 2 h, then concentrated in vacuo. Theresidue was purified by reverse-phase HPLC, eluting with a 20-80%gradient of acetonitrile in water with 0.1% formic acid over 14 minutesat 60 mL/min to afford the title compound as a colorless solid (0.097 g,78% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 7.98 (dd, J=6.2, 1.9 Hz, 1H),7.80-7.71 (m, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.29-7.07 (br s, 1H), 6.80(d, J=13.0 Hz, 1H), 4.11 (d, J=20.7 Hz, 2H), 3.66 (s, 2H), 3.06-2.93 (m,1H), 2.67 (d, J=11.5 Hz, 2H), 2.31 (t, J=10.4 Hz, 2H), 2.01-1.81 (m,4H), 1.78-1.65 (m, 1H), 1.23-0.93 (m, 4H), 0.90-0.78 (m, 2H), 0.59-0.46(m, 2H) (Note: exchangeable proton not observed); MS (ES+) m/z 624.1,626.1 (M+1).

Example 20 Synthesis ofN-(cyclopropanesulfonimidoyl)-3-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)benzamide

Step 1. Preparation of tert-butyl4-((4-(tert-butoxycarbonyl)-2-chlorophenoxy)methyl)piperidine-1-carboxylate

To a solution of tert-butyl 3-chloro-4-fluorobenzoate (9.59 g, 41.7mmol) and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (8.90 g,41.3 mmol) in anhydrous dimethylsulfoxide (100 mL) was added cesiumcarbonate (26.9 g, 82.6 mmol). The mixture was heated to 80° C. under anitrogen atmosphere for 18 h, then cooled to ambient temperature. Themixture was diluted with ethyl acetate (400 mL) and washed with brine(2×400 mL), the dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to afford the title compound as a colorless syrup(16.55 g, 94% yield).

Step 2. Preparation of tert-butyl3-cyclopropyl-4-(piperidin-4-ylmethoxy)benzoate

To a solution of tert-butyl4-((4-(tert-butoxycarbonyl)-2-chlorophenoxy)methyl)piperidine-1-carboxylate(17.8 g, 41.8 mmol) in toluene (300 mL) and water (30 mL) was addedcyclopropylboronic acid (14.2 g, 167.4 mmol), tribasic potassiumphosphate (35.5 g, 167.4 mmol), tricyclohexylphosphine tetrafluoroborate(5.9 g, 8.36 mmol), and bis(triphenylphosphine)-palladium(II) dichloride(6.1 g, 16.7 mmol). The mixture was degassed with argon, then heated toreflux under a nitrogen atmosphere for 18 h. The reaction was cooled toambient temperature and filtered through a pad of diatomaceous earththat was rinsed with ethyl acetate (200 mL). The filtrate was washedwith brine (2×300 mL), dried over anhydrous sodium sulfate, filtered,and concentrated in vacuo. The residue was purified by columnchromatography, eluting with a 0-15% gradient of ethyl acetate inhexanes. The resulting compound was dissolved in 1,4-dioxane (200 mL) towhich was added 4 M hydrochloric acid in 1,4-dioxane (35 mL, 140 mmol).The solution was stirred at ambient temperature for 48 h, thenconcentrated in vacuo to afford the title compound as a colorless solidas a hydrochloride salt (15.8 g, quant. yield): MS (ES+) m/z 332.3(M+1).

Step 3. Preparation of tert-butyl(S)-3-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)benzoate

To a solution of (R)-1-(3,5-dichlorophenyl)ethan-1-ol (1.04 g, 5.44mmol) in 4-methyl-2-pentanone (10.5 mL) was added methanesulfonicanhydride (1.40 g, 8.03 mmol). The solution was cooled to 0° C. to whichtriethylamine (1.24 mL, 8.89 mmol) was slowly added. The solution waswarmed to ambient temperature while stirring under a nitrogen atmospherefor 30 minutes and was then washed with saturated aqueous ammoniumchloride (2×15 mL) and water (2×15 mL). Separately, tert-butyl3-cyclopropyl-4-(piperidin-4-ylmethoxy)benzoate hydrochloride (1.59 g,4.34 mmol) was dissolved in 4-methyl-2-pentanone (16 mL) to which wasadded 0.5 M sodium hydroxide (11.1 mL, 5.55 mmol). The mixture washeated to 50° C. for 5 minutes, then cooled to ambient temperature. Theorganic layer was removed and concentrated in vacuo to ¼ volume, thencombined with the above solution of mesylate. To this was added water(2.5 mL) and potassium carbonate (1.17 g, 8.47 mmol) and the mixture washeated to 85° C. After 18 h, the mixture was cooled to ambienttemperature, diluted with 0.2 M sodium hydroxide (50 mL) and extractedwith ethyl acetate (4×50 mL). The combined organic extracts were driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo.The residue was purified by column chromatography, eluting with a 20-35%gradient of ethyl acetate in hexanes to afford the title compound as acolorless syrup (1.91 g, 87% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.77 (dd,J=2.2, 8.6 Hz, 1H), 7.50 (d, J=2.1 Hz, 1H), 7.25 (br s, 3H), 6.79 (d,J=8.6 Hz, 1H), 3.89 (d, J=6.0 Hz, 2H), 3.45-3.38 (m, 1H), 3.09-3.02 (m,1H), 2.87-2.80 (m, 1H), 2.19-1.78 (m, 6H), 1.73-1.70 (m, 1H), 1.58 (s,9H), 1.51-1.48 (m, 1H), 1.36 (d, J=6.9 Hz, 3H), 0.96-0.90 (m, 2H),0.72-0.67 (m, 2H); MS (ES+) m/z 504.2, 506.2 (M+1).

Step 4. Preparation of(S)-3-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)benzoicacid

To tert-butyl(S)-3-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)benzoate(1.91 g, 3.78 mmol) was added 4 M hydrochloric acid in 1,4-dioxane (19mL). The mixture was stirred at ambient temperature for 18 h, thenconcentrated in vacuo. The residue was triturated in diethyl ether (30mL) to afford the title compound as a colorless solid as a hydrochloridesalt (1.18 g, 64% yield).

Step 5. Preparation ofN-(tert-butyldimethylsilyl)-N-(cyclopropanesulfonimidoyl)-3-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)benzamide

Following the procedure as described in Example 8, Step 1 and makingnon-critical variations as required to replace4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2,5-difluorobenzoic acid with(S)-3-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)benzoicacid, the title compound was obtained as a colorless solid (0.30 g, 63%yield): MS (ES+) m/z 664.4, 666.3 (M+1).

Step 6. Preparation ofN-(cyclopropanesulfonimidoyl)-3-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)benzamide

Following the procedure as described in Example 19, step 2 and makingnon-critical variations as required to replaceN-(tert-butyldimethylsilyl)-4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)-benzyl)-4-fluoropiperidin-4-yl)methoxy)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamidewithN-(tert-butyldimethylsilyl)-N-(cyclopropanesulfonimidoyl)-3-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)benzamide,the title compound was obtained as a colorless solid (0.028 g, 11%yield): ¹H NMR (300 MHz, DMSO-d₆) δ 7.72 (dd, J=8.5, 2.1 Hz, 1H), 7.43(t, J=1.9 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.32 (d, J=1.9 Hz, 2H), 7.20(br s, 2H), 6.89 (d, J=8.7 Hz, 1H), 3.85 (d, J=5.7 Hz, 2H), 3.52 (q,J=6.6 Hz, 1H), 3.10-2.98 (m, 1H), 2.90 (d, J=10.7 Hz, 1H), 2.75 (d,J=11.0 Hz, 1H), 2.11-2.00 (m, 1H), 1.98-1.56 (m, 5H), 1.41-1.27 (m, 1H),1.25 (d, J=6.7 Hz, 3H), 1.20-1.14 (m, 1H), 1.17-1.08 (m, 1H), 1.06-0.94(m, 3H), 0.91-0.82 (m, 2H), 0.55 (q, J=5.8 Hz, 2H); MS (ES+) m/z 550.1,552.1 (M+1).

Example 21 Synthesis ofN-(cyclopropanesulfonimidoyl)-5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide

Step 1. Preparation of tert-butyl(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoate

Following the procedure as described in Example 20, step 3 and makingnon-critical variations as required to replace tert-butyl3-cyclopropyl-4-(piperidin-4-ylmethoxy)benzoate with tert-butyl5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate (preparedaccording to International Patent Application Publication NumberWO2015078374), the title compound was obtained as a colorless syrup(7.49 g, 55% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.39 (d, J=8.6 Hz, 1H),7.25-7.24 (m, 3H), 6.51 (d. J=12.7 Hz, 1H), 3.84 (d, J=6.1 Hz, 2H),3.45-3.38 (m, 1H), 3.08-3.02 (m, 1H), 2.87-2.80 (m, 1H), 2.08-1.78 (m,6H), 1.72-1.70 (m, 1H), 1.58 (s. 9H), 1.51-1.49 (m, 1H), 1.35 (d, J=6.7Hz, 3H), 0.94-0.87 (m, 2H), 0.67-0.62 (m, 2H); MS (ES+) m/z 522.2, 524.2(M+1).

Step 2. Preparation ofN-(tert-butyldimethylsilyl)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide

Following the procedures as described in Example 20, step 4 then Example8, step 1 and making non-critical variations as required to replacetert-butyl(S)-3-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)benzoatewith tert-butyl(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoate,the title compound was obtained as a colorless solid (0.047 g, 8%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.58 (d, J=9.0 Hz, 1H), 7.25-7.24 (m,3H), 6.55 (d, J=13.9 Hz, 1H), 3.86 (d, J=5.9 Hz, 2H), 3.47-3.40 (m, 1H),3.10-3.02 (m, 2H), 2.89-2.82 (m, 1H), 2.62-2.53 (m, 1H), 2.10-1.59 (m,8H), 1.36 (d, J=6.7 Hz, 3H), 1.31-1.25 (m, 2H), 1.06-1.01 (m, 2H),0.95-0.92 (m, 11H), 0.71-0.65 (m, 2H), 0.16 (s, 6H); MS (ES+) m/z 682.2,684.1 (M+1).

Step 3. Preparation ofN-(cyclopropanesulfonimidoyl)-5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide

Following the procedure as described in Example 19, step 2 and makingnon-critical variations as required to replaceN-(tert-butyldimethylsilyl)-4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)-benzyl)-4-fluoropiperidin-4-yl)methoxy)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-2-fluorobenzamidewithN-(tert-butyldimethylsilyl)-N-(cyclopropanesulfonimidoyl)-5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide,the title compound was obtained as a colorless solid (0.003 g, 9%yield): ¹H NMR (300 MHz, DMSO-d₆) δ 7.44 (t, J=1.8 Hz, 1H), 7.32 (dd,J=5.2, 3.4 Hz, 3H), 7.23 (br s, 2H), 6.74 (d, J=13.1 Hz, 1H), 3.85 (d,J=5.7 Hz, 2H), 3.51 (q, J=6.9 Hz, 1H), 3.06-2.95 (m, 1H), 2.89 (d,J=11.2 Hz, 1H), 2.75 (d, J=11.5 Hz, 1H), 2.02-1.82 (m, 3H), 1.81-1.60(m, 3H), 1.38-1.31 (m, 1H), 1.25 (d, J=6.7 Hz, 3H), 1.23-1.10 (m, 2H),1.08-0.96 (m, 3H), 0.89-0.79 (m, 2H), 0.52 (q, J=5.9 Hz, 2H); ¹⁹F NMR(282 MHz, CDCl₃) δ −111.2 (s, 1F); MS (ES+) m/z 568.2, 570.2 (M+1).

Example 22 Electrophysiological Assay (EP) (In Vitro Assay)

Patch voltage clamp electrophysiology allows for the direct measurementand quantification of block of voltage-gated sodium channels (NaV's),and allows the determination of the time- and voltage-dependence ofblock which has been interpreted as differential binding to the resting,open, and inactivated states of the sodium channel (Hille, B., Journalof General Physiology (1977), 69: 497-515).

The following patch voltage clamp electrophysiology studies wereperformed on representative compounds of the invention using humanembryonic kidney cells (HEK), permanently transfected with an expressionvector containing the full-length cDNA coding for the desired humansodium channel α-subunit, grown in culture media containing 10% FBS, 1%PSG, and 0.5 mg/mL G418 at 37° C. with 5% CO2. HEK cells used for theelectrophysiology (EP) recordings had a passage number of less than 40for all studies and were used within three days from the time ofplating. NaV1.7 and NaV1.5 cDNAs (NM_002977 and AC137587; SCN5A,respectively) were stably expressed in HEK-293 cells. The β1 subunit wascoexpressed in both the NaV1.7 and NaV1.5 cell lines.

Sodium currents were measured using the patch clamp technique in thewhole-cell configuration using either a PatchXpress automated voltageclamp or manually using an Axopatch 200B (Axon Instruments) or Model2400 (A-M systems) amplifier. The manual voltage clamp protocol was asfollows: Borosilicate glass micropipettes were fire-polished to a tipdiameter yielding a resistance of 2-4 Mohms in the working solutions.The pipette was filled with a solution comprised of: 5 mM NaCl, 10 mMCsCl, 120 mM CsF, 0.1 mM CaCl2, 2 mM MgCl2, 10 mM HEPES, 10 mM EGTA; andadjusted to pH 7.2 with CsOH. The external solution had the followingcomposition: 140 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES;and adjusted to pH 7.4 with NaOH. In some studies, the external sodiumwas reduced by equimolar replacement with choline. Osmolarity in the CsFinternal and NaCl external solutions was adjusted to 300 mOsm/kg and 310mOsm/kg with glucose, respectively. All recordings were performed atambient temperature in a bath chamber with a volume of 150 μL. Controlsodium currents were measured in 0.5% DMSO. Controls and representativecompounds of the invention were applied to the recording chamber througha 4-pinch or 8-pinch valve bath perfusion system manufactured by ALAScientific Instruments.

Currents were recorded at 40 kHz sampling frequency, filtered at 5 Hz,and stored using a Digidata-1322A analogue/digital interface with thepClamp software (Axon Instruments). Series resistance compensation wasapplied (60-80%). Cells were rejected if currents showed inadequatevoltage control (as judged by the IV relationship during stepwiseactivation). All statistics in this study are given as mean±SD.

The membrane potential was maintained at a voltage where inactivation ofthe channel is complete (which was −60 mV for both NaV1.7 and NaV1.5).The voltage is then stepped back to a very negative (Vhold=150 mV)voltage for 20 ms and then a test pulse is applied to quantify thecompound block. The 20 ms brief repolarization was long enough forcompound-free channels to completely recover from fast inactivation, butthe compound-bound channels recovered more slowly such that negligiblerecovery could occur during this interval. The percent decrease insodium current following wash-on of compound was taken as the percentblock of sodium channels. Data for representative compounds of formula(I) is provided in Table 1.

Example 23 Tritiated Sulfonamide Binding to Membranes

isolated from cells that heterologously express hNav1.7 and the β1subunit Preparation of membranes containing recombinantly expressedsodium channels: Frozen recombinant cell pellets were thawed on ice anddiluted to 4 times the cell pellet weight with ice cold 50 mM Tris HCl,pH 7.4 buffer. The cell suspensions were homogenized on ice using amotorized glass dounce homogeniser. Homogenates were further diluted 8.4times with ice cold 50 mM Tris HCl, pH 7.4 buffer and then centrifugedat 200×g at 4° C. for 15 min. The supernatants were collected andcentrifuged at 10000×g at 4° C. for 50 min. The pellets were thenre-suspended in 100 mM NaCl, 20 mM Tris HCl, pH 7.4 buffer containing 1%v/v protease inhibitors (Calbiochem) and re-homogenized on ice. Thehomogenized membranes were then processed through a syringe equippedwith a 26 gauge needle. Protein concentrations were determined byBradford Assay and the membranes were stored at −80° C.

Radioligand Binding Studies:

Saturation experiments. A representative compound of formula (I) havinga methyl group was tritiated. Three tritiums were incorporated in placeof methyl hydrogens to generate [³H]compound. Binding of thisradioligand was preformed in 5 mL borosilicate glass test tubes at roomtemperature. Binding was initiated by adding membranes to increasingconcentrations of [³H]compound in 100 mM NaCl, 20 mM Tris HCl, pH 7.4buffer containing 0.01% w/v bovine serum albumin (BSA) for 18 h.Non-specific binding was determined in the presence of 1 μM unlabelledcompound. After 18 h, the reactants were filtered through GF/C glassfiber filters presoaked in 0.5% w/v polyethylene imine. Filters werewashed with 15 mL ice cold 100 mM NaCl, 20 mM Tris HCl, pH7.4 buffercontaining 0.25% BSA to separate bound from free ligand. [³H]compoundbound to filters was quantified by liquid scintillation counting.

Competitive Binding Experiments:

Binding reactions were preformed in 96-well polypropylene plates at roomtemperature for 18 h. In 360 μL, membranes were incubated with 100 pM[³H]compound and increasing concentrations of Test Compound.Non-specific binding was defined in the presence of 1 μM unlabelledcompound. Reactions were transferred and filtered through 96-well glassfiber/C filter plates presoaked with 0.5% polyethylene imine. Thefiltered reactions were washed 5 times with 200 μL ice cold buffercontaining 0.25% BSA. Bound radioactivity was determined by liquidscintillation counting.

Data Analysis: For saturation experiments, non-specific binding wassubtracted from total binding to provide specific binding and thesevalues were recalculated in terms of pmol ligand bound per mg protein.Saturation curves were constructed and dissociation constants werecalculated using the single site ligand binding model:Beq=(Bmax*X)/(X+Kd), where Beq is the amount of ligand bound atequilibrium, Bmax is the maximum receptor density, Kd is thedissociation constant for the ligand, and X is the free ligandconcentration. For competition studies percent inhibition was determinedand IC₅₀ values were calculated using a 4 parameter logistic model (%inhibition=(A+((B−A)/(1+((x/C){circumflex over ( )}D)))) using XLfit,where A and B are the maximal and minimum inhibition respectively, C isthe IC₅₀ concentration and D is the (Hill) slope.

Representative compounds, when tested in this model, demonstratedaffinities as set forth in Table 1.

TABLE 1 NaV1.7 395 Memb EP_QP 293 EP_QB 293 Binding XE hNaV1.7 hNaV 1.7Example Structure (IC₅₀) XE (IC₅₀) XE (IC₅₀) 1

0.0221 0.0224 0.206 2

2.61 3

0.00576 0.0032 0.0478 4

0.112 5

0.0229 6

1.43 7

0.132 8

0.238 9

0.0238 10

0.00867 11

0.0142 12

0.159 13

0.0809 14

0.0236 15

0.0198 16

0.0181 17

2.29 18

0.21 19

0.182 20

0.616 21

0.0925

Example 24 Analgesia Induced by Sodium Channel Blockers

Heat Induced Tail Flick Latency Test

In this test, the analgesia effect produced by administering a compoundof the invention can be observed through heat-induced tail-flick inmice. The test includes a heat source consisting of a projector lampwith a light beam focused and directed to a point on the tail of a mousebeing tested. The tail-flick latencies, which are assessed prior to drugtreatment, and in response to a noxious heat stimulus, i.e., theresponse time from applying radiant heat on the dorsal surface of thetail to the occurrence of tail flick, are measured and recorded at 40,80, 120, and 160 minutes.

For the first part of this study, 65 animals undergo assessment ofbaseline tail flick latency once a day over two consecutive days. Theseanimals are then randomly assigned to one of the 11 different treatmentgroups including a vehicle control, a morphine control, and 9 compoundsat 30 mg/Kg are administered intramuscularly. Following doseadministration, the animals are closely monitored for signs of toxicityincluding tremor or seizure, hyperactivity, shallow, rapid or depressedbreathing and failure to groom. The optimal incubation time for eachcompound is determined via regression analysis. The analgesic activityof the test compounds is expressed as a percentage of the maximumpossible effect (% MPE) and is calculated using the following formula:

$\%\mspace{14mu}{MPE}\frac{{{Postdrug}\mspace{14mu}{latency}} - {{Predrug}\mspace{14mu}{latency}}}{{{Cut}\text{-}{off}\mspace{14mu}{time}\mspace{14mu}\left( {10\mspace{14mu} s} \right)} - {{Predrug}\mspace{14mu}{latency}}} \times 100\%$where:

Postdrug latency=the latency time for each individual animal takenbefore the tail is removed (flicked) from the heat source afterreceiving drug.

Predrug latency=the latency time for each individual animal taken beforethe tail is flicked from the heat source prior to receiving drug.

Cut-off time (10 s)=is the maximum exposure to the heat source.

Acute Pain (Formalin Test)

The formalin test is used as an animal model of acute pain. In theformalin test, animals are briefly habituated to the plexiglass testchamber on the day prior to experimental day for 20 minutes. On the testday, animals are randomly injected with the test articles. At 30 minutesafter drug administration, 50 μL of 10% formalin is injectedsubcutaneously into the plantar surface of the left hind paw of therats. Video data acquisition begins immediately after formalinadministration, for duration of 90 minutes.

The images are captured using the Actimetrix Limelight software whichstores files under the *.llii extension, and then converts it into theMPEG-4 coding. The videos are then analyzed using behaviour analysissoftware “The Observer 5.1”, (Version 5.0, Noldus InformationTechnology, Wageningen, The Netherlands). The video analysis isconducted by watching the animal behaviour and scoring each according totype, and defining the length of the behaviour (Dubuisson and Dennis,1977). Scored behaviours include: (1) normal behaviour, (2) putting noweight on the paw, (3) raising the paw, (4) licking/biting or scratchingthe paw. Elevation, favoring, or excessive licking, biting andscratching of the injected paw indicate a pain response. Analgesicresponse or protection from compounds is indicated if both paws areresting on the floor with no obvious favoring, excessive licking, bitingor scratching of the injected paw.

Analysis of the formalin test data is done according to two factors: (1)Percent Maximal Potential Inhibitory Effect (% MPIE) and (2) pain score.The % MPIEs is calculated by a series of steps, where the first is tosum the length of non-normal behaviours (behaviours 1,2,3) of eachanimal. A single value for the vehicle group is obtained by averagingall scores within the vehicle treatment group. The following calculationyields the MPIE value for each animal:MPIE (%)=100−[(treatment sum/average vehicle value)×100%]

The pain score is calculated from a weighted scale as described above.The duration of the behaviour is multiplied by the weight (rating of theseverity of the response), and divided by the total length ofobservation to determine a pain rating for each animal. The calculationis represented by the following formula:Pain rating=[0(To)+1(T1)+2(T2)+3(T3)]/(To+T1+T2+T3)

CFA Induced Chronic Inflammatory Pain

In this test, tactile allodynia is assessed with calibrated von Freyfilaments. Following a full week of acclimatization to the vivariumfacility, 150 μL of the “Complete Freund's Adjuvant” (CFA) emulsion (CFAsuspended in an oil/saline (1:1) emulsion at a concentration of 0.5mg/mL) is injected subcutaneously into the plantar surface of the lefthind paw of rats under light isoflurane anaesthesia. Animals are allowedto recover from the anaesthesia and the baseline thermal and mechanicalnociceptive thresholds of all animals are assessed one week after theadministration of CFA. All animals are habituated to the experimentalequipment for 20 minutes on the day prior to the start of theexperiment. The test and control articles are administrated to theanimals, and the nociceptive thresholds measured at defined time pointsafter drug administration to determine the analgesic responses to eachof the six available treatments. The time points used are previouslydetermined to show the highest analgesic effect for each test compound.

Thermal nociceptive thresholds of the animals are assessed using theHargreaves test. Animals are placed in a Plexiglas enclosure set on topof an elevated glass platform with heating units. The glass platform isthermostatically controlled at a temperature of approximately 30° C. forall test trials. Animals are allowed to accommodate for 20 minutesfollowing placement into the enclosure until all exploration behaviourceases. The Model 226 Plantar/Tail Stimulator Analgesia Meter (IITC,Woodland Hills, Calif.) is used to apply a radiant heat beam fromunderneath the glass platform to the plantar surface of the hind paws.During all test trials, the idle intensity and active intensity of theheat source are set at 1 and 45 respectively, and a cut off time of 20seconds is employed to prevent tissue damage.

The response thresholds of animals to tactile stimuli are measured usingthe Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.) following the Hargreaves test. Animals areplaced in an elevated Plexiglas enclosure set on a mire mesh surface.After 10 minutes of accommodation, pre-calibrated Von Frey hairs areapplied perpendicularly to the plantar surface of both paws of theanimals in an ascending order starting from the 0.1 g hair, withsufficient force to cause slight buckling of the hair against the paw.Testing continues until the hair with the lowest force to induce a rapidflicking of the paw is determined or when the cut off force ofapproximately 20 g is reached. This cut off force is used because itrepresent approximately 10% of the animals' body weight and it serves toprevent raising of the entire limb due to the use of stiffer hairs,which would change the nature of the stimulus.

Postoperative Models of Nociception

In this model, the hypealgesia caused by an intra-planar incision in thepaw is measured by applying increased tactile stimuli to the paw untilthe animal withdraws its paw from the applied stimuli. While animals areanaesthetized under 3.5% isofluorane, which is delivered via a nosecone, a 1 cm longitudinal incision is made using a number 10 scalpelblade in the plantar aspect of the left hind paw through the skin andfascia, starting 0.5 cm from the proximal edge of the heel and extendingtowards the toes. Following the incision, the skin is apposed using 2,3-0 sterilized silk sutures. The injured site is covered with Polysporinand Betadine. Animals are returned to their home cage for overnightrecovery.

The withdrawal thresholds of animals to tactile stimuli for bothoperated (ipsilateral) and unoperated (contralateral) paws can bemeasured using the Model 2290 Electrovonfrey anesthesiometer (IITC LifeScience, Woodland Hills, Calif.). Animals are placed in an elevatedPlexiglas enclosure set on a mire mesh surface. After at least 10minutes of acclimatization, pre-calibrated Von Frey hairs are appliedperpendicularly to the plantar surface of both paws of the animals in anascending order starting from the 10 g hair, with sufficient force tocause slight buckling of the hair against the paw. Testing continuesuntil the hair with the lowest force to induce a rapid flicking of thepaw is determined or when the cut off force of approximately 20 g isreached. This cut off force is used because it represent approximately10% of the animals' body weight and it serves to prevent raising of theentire limb due to the use of stiffer hairs, which would change thenature of the stimulus.

Neuropathic Pain Model; Chronic Constriction Injury

Briefly, an approximately 3 cm incision is made through the skin and thefascia at the mid thigh level of the animals' left hind leg using a no.10 scalpel blade. The left sciatic nerve is exposed via blunt dissectionthrough the biceps femoris with care to minimize haemorrhagia. Fourloose ligatures are tied along the sciatic nerve using 4-0non-degradable sterilized silk sutures at intervals of 1 to 2 mm apart.The tension of the loose ligatures is tight enough to induce slightconstriction of the sciatic nerve when viewed under a dissectionmicroscope at a magnification of 4 fold. In the sham-operated animal,the left sciatic nerve is exposed without further manipulation.Antibacterial ointment is applied directly into the wound, and themuscle is closed using sterilized sutures. Betadine is applied onto themuscle and its surroundings, followed by skin closure with surgicalclips.

The response thresholds of animals to tactile stimuli are measured usingthe Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.). Animals are placed in an elevated Plexiglasenclosure set on a mire mesh surface. After 10 minutes of accommodation,pre-calibrated Von Frey hairs are applied perpendicularly to the plantarsurface of both paws of the animals in an ascending order starting fromthe 0.1 g hair, with sufficient force to cause slight buckling of thehair against the paw. Testing continues until the hair with the lowestforce to induce a rapid flicking of the paw is determined or when thecut off force of approximately 20 g is reached. This cut off force isused because it represents approximately 10% of the animals' body weightand it serves to prevent raising of the entire limb due to the use ofstiffer hairs, which would change the nature of the stimulus.

Thermal nociceptive thresholds of the animals are assessed using theHargreaves test. Following the measurement of tactile thresholds,animals are placed in a Plexiglass enclosure set on top of an elevatedglass platform with heating units. The glass platform isthermostatically controlled at a temperature of approximately 24 to 26°C. for all test trials. Animals are allowed to accommodate for 10minutes following placement into the enclosure until all explorationbehaviour ceases. The Model 226 Plantar/Tail Stimulator Analgesia Meter(IITC, Woodland Hills, Calif.) is used to apply a radiant heat beam fromunderneath the glass platform to the plantar surface of the hind paws.During all test trials, the idle intensity and active intensity of theheat source are set at 1 and 55 respectively, and a cut off time of 20seconds is used to prevent tissue damage.

Neuropathic Pain Model: Spinal Nerve Ligation

The spinal nerve ligation (SNL) neuropathic pain model is used as ananimal (i.e. rat) model of neuropathic pain. In the SNL test, the lumbarroots of spinal nerves L5 and L6 are tightly ligated to cause nerveinjury, which results in the development of mechanical hyperalgesia,mechanical allodynia and thermal hypersensitivity. The surgery isperformed two weeks before the test day in order for the pain state tofully develop in the animals. Several spinal nerve ligation variationsare used to characterize the analgesic properties of a compound of theinvention.

Ligation of the L5 spinal nerve;

Ligation of the L5 and L6 spinal nerves;

Ligation and transection of the L5 spinal nerve;

Ligation and transection of the L5 and L6 spinal nerves; or

Mild irritation of the L4 spinal nerve in combination with any one ofthe above (1)-(4).

While the animals are anaesthetized under 3.5% isofluorane delivered viaa nose cone, an approximately 2.5 cm longitudinal incision is made usinga number 10 scalpel blade in the skin just lateral to the dorsalmidline, using the level of the posterior iliac crests as the midpointof the incision. Following the incision, the isoflourane is readjustedto maintenance levels (1.5%-2.5%). At mid-sacral region, an incision ismade with the scalpel blade, sliding the blade along the side of thevertebral column (in the saggital plane) until the blade hits thesacrum. Scissors tips are introduced through the incision and the muscleand ligaments are removed from the spine to expose 2-3 cm of thevertebral column. The muscle and fascia are cleared from the spinalvertebra in order to locate the point where the nerve exits from thevertebra. A small glass hook is placed medial to the spinal nerves andthe spinal nerves are gently elevated from the surrounding tissues. Oncethe spinal nerves have been isolated, a small length of non-degradable6-0 sterilized silk thread is wound twice around the ball at the tip ofthe glass hook and passed back under the nerve. The spinal nerves arethen firmly ligated by tying a knot, ensuring that the nerve bulges onboth sides of the ligature. The procedure may be repeated as needed. Insome animals, the L4 spinal nerve may be lightly rubbed (up to 20 times)with the small glass hook to maximize the development of neuropathicpain. Antibacterial ointment is applied directly into the incision, andthe muscle is closed using sterilized sutures. Betadine is applied ontothe muscle and its surroundings, followed by skin closure with surgicalstaples or sterile non-absorable monofilament 5-0 nylon sutures.

The analgesic effect produced by topical administration of a compound ofthe invention to the animals can then be observed by measuring the pawwithdrawal threshold of animals to mechanical tactile stimuli. These maybe measured using either the mechanical allodynia procedure or themechanical hyperalgesia procedure as described below. Afterestablishment of the appropriate baseline measurements by either method,topical formulation of a compound of the invention is applied on theipsilateral ankle and foot. The animals are then placed in plastictunnels for 15 minutes to prevent them from licking the treated area andremoving the compound. Animals are placed in the acrylic enclosure for15 minutes before testing the ipsilateral paw by either of the methodsdescribed below, and the responses are recorded at 0.5, 1.0 and 2.0 hourpost treatment.

Mechanical Allodynia Method

The pain threshold of animals to mechanical alloydnia for both operatedand control animals can be measured approximately 14 days post-surgeryusing manual calibrated von Frey filaments as follows. Animals areplaced in an elevated plexiglass enclosure set on a mire mesh surface.Animals are allowed to acclimate for 20-30 minutes. Pre-calibrated VonFrey hairs are applied perpendicularly to the plantar surface of theipsilateral paw of the animals starting from the 2.0 g hair, withsufficient force to cause slight buckling of the hair against the paw toestablish the baseline measurements. Stimuli are presented in aconsecutive manner, either in an ascending or descending order until thefirst change in response is noted, after which four additional reponsesare recorded for a total of six responses. The six responses measured ingrams are entered into a formula as described by Chaplan, S. R. et al.,J. Neurosci. Methods, 1994 July; 53(1):55-63, and a 50% withdrawalthreshold is calculated. This constitutes the mechanical allodyniavalue.

B. Mechanical Hyperalgesia Method

The response thresholds of animals to tactile stimuli were measuredusing the Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.). Animals were placed in an elevated Plexiglasenclosure set on a wire mesh surface. After 15 minutes of accommodationin this enclosure, a von Frey hair was applied perpendicularly to theplantar surface of the ipsilateral hind paws of the animals, withsufficient force, measured in grams, to elicit a crisp response of thepaw. The response indicated a withdrawal from the painful stimulus andconstituted the efficacy endpoint. The data were expressed as percentchange from baseline threshold measured in grams.

Example 25 In Vivo Assay for Treatment of Pruritis

The compounds of the invention can be evaluated for their activity asantipruritic agents by in vivo test using rodent models. One establishedmodel for peripherally elicited pruritus is through the injection ofserotonin into the rostral back area (neck) in hairless rats. Prior toserotonin injections (e.g., 2 mg/mL, 50 μL), a dose of a compound of thepresent invention can be applied systemically through oral, intravenousor intraperitoneal routes or topically to a circular area fixed diameter(e.g. 18 mm). Following dosing, the serotonin injections are given inthe area of the topical dosing. After serotonin injection the animalbehaviour is monitored by video recording for 20 min-1.5 h, and thenumber of scratches in this time compared to vehicle treated animals.Thus, application of a compound of the current invention could suppressserotonin-induced scratching in rats.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon patent publications referred to in this specification areincorporated herein by reference in their entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

We claim:
 1. A compound of formula I:

or a salt thereof wherein: R¹ is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈haloalkyl, C₁₋₈ alkoxy, 3-20 membered carbocycle, C-linked 3-20 memberedheterocycle, or —NR^(1A)R^(1B), herein R^(1A) and R^(1B) are eachindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₁₋₈ alkoxy, and wherein R^(1A) and R^(1B) are optionallycombined to form a 3-20 membered heterocycle; and wherein R¹ isoptionally substituted with from 1 to 5 substituents selected from thegroup consisting of C₁₋₄ alkyl, C₃₋₄ haloalkyl, F, Cl, Br, I, —OH, —CN,—NO₂, —NR^(R1a)R^(R1b), —OR^(R1a), —SR^(R1a), —Si(R^(R1a))₃ and C₃₋₆carbocycle; wherein R^(R1a) and R^(R1b) are independently selected fromthe group consisting of hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl; R^(N)is hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; L is a linker selected fromthe group consisting of C₁₋₄ alkylene, C₂₋₄ alkenylene and C₂₋₄alkynylene, wherein L is optionally substituted with from 1 to 3substituents selected from the group consisting of ═O, C₁₋₄ alkyl, halo,and C₁₋₄ haloalkyl; the subscript m is 0 or 1; X¹ and X² are eachindependently selected from the group consisting of absent, —O—, —S(O)—,—S(O)₂— and —N(R^(X))— wherein R^(x) is H, C₁₋₈ alkyl, C₁₋₈ alkanoyl, or—S(O)₂(C₁₋₈ alkyl), and wherein if the subscript m is 0 then one of X¹or X² is absent; the subscript n is 0, 1, 2, 3, 4, or 5; the ring A is a3-20 membered carbocyclyl, a 6-20 membered aryl, a 5-20 memberedheteroaryl, or a 3-20 membered heterocyclyl; each R^(AA) isindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ heteroalkyl, CN, F, Cl, Br and I; and R^(A) is selectedfrom the group consisting of absent, CN, F, Cl, Br, I,R^(A1)O—(X^(RB))—, (3-20 membered aryl)-(X^(RA))—, (3-20 memberedheteroaryl)-(X^(RA))—, (3-20 membered carbocycle)-(X^(RA))—, (3-20membered heterocycle)-(X^(RA))—, —R^(A2), and —S(O)₂—R^(A2), whereinsaid 3-20 membered aryl, 3-20 membered heteroaryl, 3-20 memberedcarbocycle and 3-20 membered heterocycle of R^(A) is optionallysubstituted with from 1 to 5 substitutents selected from, F, Cl, Br, I,—NH₂, —OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,C₁₋₄(halo)alkoxy, C₁₋₄ alkylamino, C₁₋₄ dialkylamino, C₁₋₄ alkanoyl,C₁₋₄ akyl-OC(═O)—, C₁₋₄ alkyl-S(O)₂—, C₃₋₆ carbocycle, and phenyl thatis optionally substituted with one or more substituents selected fromfluoro, chloro, and bromo; R^(A1) is selected from the group consistingof hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl,phenyl and benzyl; R^(A2) is a C₁₋₈ alkyl that is optionally substitutedwith one or more substituents selected from oxo (═O), fluoro, amino,C₁₋₄ alkylamino and C₁₋₄ dialkylamino; X^(RA) is selected from the groupconsisting of absent, —O—, —S—, —N(H)—, —N(C₁₋₄ alkyl)-, —S(O)—,—S(O)₂—, —C(═O)—, C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenyleneand C₂₋₄ alkynylene; X^(RB) is selected from the group consisting ofabsent, C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄alkynylene; wherein any C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene of X^(RA) or X^(RB) is optionallysubstituted with 1 to 3 substituents selected from the group consistingof C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ heteroalkyl, oxo (═O), hydroxy, andphenyl that is optionally substituted with 1 to 5 substitutents selectedfrom, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, C₁₋₄(halo)alkoxy, C₁₋₄ alkylamino and C₁₋₄ dialkylamino; orwherein X^(RA) or X^(RB) is optionally substituted with 2 substituentsthat combine to form a 3-5 membered carbocycle or a 3-5 memberedheterocycle; the ring B is selected from:

D¹ is N or C(R^(D1)); D³ is N or C(R^(D3)); R^(D1), R^(D2), R^(D3) andR^(D4) are each independently selected from the group consisting of H,F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, 3-12membered cycloalkyl, 3-12 membered heterocycle, phenyl and 5-6 memberedheteroaryl comprising 1 to 3 heteroatoms selected from N, O and S,wherein said 5-6 membered heteroaryl is further optionally substitutedwith from 1 to 3 substituents selected from F, Cl, Br, I, —CN, C₁₋₄alkyl, C₁₋₄ haloalkyl and C₁₋₄ alkoxy; R²² and R²³ are eachindependently selected from the group consisting of H, F, Cl, Br, I,—CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy; R²⁴ is selected fromthe group consisting of H, F, CL, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₁₋₈ alkoxy, 3-12 membered carbocycle, 3-12 memberedheterocycle, phenyl and 5-6 membered heteroaryl comprising 1 to 3heteroatoms selected from N, O and S, wherein said 5-6 memberedheteroaryl is further optionally substituted with from 1 to 3 R⁵substituents selected from F, Cl, Br, I, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyland C₁₋₄ alkoxy; R³² and R³³ are each independently selected from thegroup consisting of H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl andC₁₋₈ alkoxy; R³⁴ is selected from the group consisting of H, F, Cl, Br,1, —CN, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, 3-12membered carbocycle, 3-12 membered heterocycle, phenyl and 5-6 memberedheteroaryl comprising 1 to 3 heteroatoms selected from N, O and S,wherein said 5-6 membered heteroaryl is further optionally substitutedwith from 1 to 3 substituents selected from F, Cl, Br, I, —CN, C₁₋₄alkyl, C₁₋₄ haloalkyl and C₁₋₄ alkoxy; R⁴² is selected from the groupconsisting of H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈alkoxy; R⁴³ is selected from the group consisting of H, F, Cl, Br, I,—CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy; R⁴⁴ is selected fromthe group consisting of H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyland C₁₋₈ alkoxy; and R⁴⁵ is selected from the group consisting of H,C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, and 3-12 membered cycloalkyl,wherein said C₁₋₈ alkoxy, and 3-12 membered cycloalkyl are optionallysubstituted with 1-3 substituents selected from F, Cl, Br and I.
 2. Thecompound of claim 1 wherein R¹ is methyl, cyclopropyl,cyclopropylmethyl, 1-azetidinyl, 1-methylcycloprop-1-yl, difluoromethyl,N-methylamino, ethyl, 2-methoxyeth-1-yl, 2-trimethylsilyleth-1-yl,propyl, 1,1,1-trifluoroprop-3-yl, butyl, morpholino, pyrrolidino, or3-fluoroazetidin-1-yl.
 3. The compound of claim 1, wherein X¹ is —O— or—N(H)—; X² is absent; the subscript m is 1; and -(L)- is selected fromthe group consisting of —CH₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—,—CH₂—C(H)(CH₃)—, —C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—, —CH₂—C(H)(CH₁₃)—CH₂— or—CH₂CH₂CH₂CH₂—.
 4. The compound of claim 1, wherein X¹ is absent; X² is—O— or —N(H)—; the subscript m is 1; and -(L)- is selected from thegroup consisting of —CH₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—,—CH₂—C(H)(CH₃)—, —C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—, —CH₂—C(H)(CH₃)—CH₂—,and —CH₂CH₂CH₂CH₂—.
 5. The compound of claim 1, wherein the ring A is a3-15 membered carbocyclyl, a 6-12 membered aryl, a 5-12 memberedheteroaryl, or a 3-15 membered heterocyclyl.
 6. The compound of claim 1,wherein A is optionally substituted and is selected from azetidine,pyrrolidine, piperidine, morpholine, homopiperazine, and piperazine. 7.The compound of claim 1, wherein the ring B is:

R^(D1) is selected from the group consisting of F, Cl, cyclopropyl, and2-methoxy-3-pyridyl; R^(D2) is H; R^(D3) is selected from the groupconsisting of F, Cl, and Br, and R^(D4) is H.
 8. The compound of claim1, wherein:

is selected from the group consisting of:


9. The compound of claim 1, wherein:

is selected from the group consisting of:


10. The compound of claim 1, wherein R^(AA) is selected from the groupconsisting of methyl, trifluoromethyl, ethyl, F, Cl, Br, and
 1. 11. Thecompound of claim 1, wherein R^(A) is selected from the group consistingof


12. The compound of claim 1, wherein the compound has the formula Ia:


13. The compound of claim 1, which is a compound of formula Ib:


14. The compound of claim 1, wherein the compound has the formula Id:


15. The compound of claim 1, wherein:

has the formula:


16. The compound of claim 1, wherein:

is selected from the group consisting of:


17. The compound of claim 1, wherein the group:

is selected from the group consisting of:


18. A pharmaceutical composition comprising a compound of formula I asdescribed in claim 1, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable excipient.
 19. The compound of claim 1which is selected from:

and salts thereof.